review article management of cardiorenal metabolic...

Review ArticleManagement of Cardiorenal Metabolic Syndrome inDiabetes Mellitus A Phytotherapeutic Perspective

Min Kyong Song1 Neal M Davies2 Basil D Roufogalis13 and Tom Hsun-Wei Huang1

1 The University of Sydney Faculty of Pharmacy Sydney NSW 2006 Australia2The University of Manitoba Faculty of Pharmacy Winnipeg MB Canada R3T 2N23The University of Sydney Discipline of Pharmacology School of Medical Sciences Sydney Medical School SydneyNSW 2006 Australia

Correspondence should be addressed to Tom Hsun-Wei Huang thwhyahoocom

Received 24 December 2013 Revised 11 March 2014 Accepted 12 March 2014 Published 13 April 2014

Academic Editor Ramesh K Goyal

Copyright copy 2014 Min Kyong Song et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleteriousdeclining functions are reinforced in a feedback cycle with an accelerated progression Although the coexistence of kidney andheart failure in the same individual carries an extremely bad prognosis the exact cause of deterioration and the pathophysiologicalmechanisms underlying the initiation and maintenance of the interaction are complex multifactorial in nature and poorlyunderstood Current therapy includes diuretics natriuretic hormones aquaretics (arginine vasopressin antagonists) vasodilatorsand inotropes However large numbers of patients still develop intractable disease Moreover the development of resistance tomany standard therapies such as diuretics and inotropes has led to an increasing movement toward utilization and developmentof novel therapies Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay theprogression of CRSThis review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeuticmedicines for the amelioration of the progression of CRS

1 Introduction

The appreciation of the interaction between kidneys andheart in disease has led to an increasing biomedical andpharmaceutical interest in recent years [1] When kidneyfailure and heart failure coexist morbidity and mortalityare negatively affected [2ndash4] Indeed cardiovascular diseaseis the leading cause of mortality consisting of 436 of alldeaths in patients with end-stage renal disease [5] Moreoverclinical and epidemiological observations have demonstratedthat both kidney failure and heart failure are associatedwith a high incidence of failure of other organs [6 7]The cardiorenal syndrome (CRS) is a complex disease inwhich both the heart and kidney are simultaneously affectedand their deleterious outcomes are reinforced in a feedbackcycle with accelerated progression [8 9] One of the mostcommon underlying risk factors for CRS are diabetes and

severe atherosclerotic vascular disease [10] Although thecoexistence of kidney and heart failure in the same individualcarries an extremely rueful prognosis the exact causes ofdeterioration and the pathophysiologicalmechanisms under-lying the initiation and maintenance of the interaction arecomplex multifactorial in nature and poorly understood[11ndash13] Plants remain as an important source of therapeuticmaterial for maintaining human health with unparalleleddiversity and they have improved the quality of humanlife through disease prevention and treatment for centuries[14] Moreover medicinal plants are an abundant sourceof biologically active molecules that play an important rolein past and modern medicine which act as a ldquosteppingstonerdquo for the discovery of novel pharmacologically activeligands [15] Current therapy of CRS includes diuretics natri-uretic hormones aquaretics (arginine vasopressin antago-nists) vasodilators and inotropesHowever large numbers of

Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2014 Article ID 313718 12 pageshttpdxdoiorg1011552014313718

2 Journal of Diabetes Research

patients still develop intractable disease [16] Moreover withthe development of resistance to many conventional thera-pies such as diuretics and inotropes there is an increasingmovement toward novel therapies [17] This has promptedmuch interest in the use of traditional medicines for thetreatment of CRS Thus the current review provides adetailed discussion summarizing the current understandingof herbal and traditional medicines for the management andpotential treatment and reversal of CRS-related pathogenesis

2 Cardiorenal Metabolic SyndromeCurrent Understanding and Classification

The CRS has been recently defined as a disorder of the heartand kidneys whereby acute or chronic dysfunction in oneorgan may induce acute or chronic dysfunction in the other[18] Several groups have proposed that each dysfunctionalorgan has the ab initio ability to initiate and perpetuatedisease in the other organ through hemodynamic neu-rohormonal and immunologicbiochemical feedback path-ways [11] Moreover the current disease definition has beenexpanded into 5 subtypes that reflect the pathophysiologytime-frame and bidirectional nature of heart and kidneyinteractions [19] Categorizing CRS based on the responseto various treatment modalities is practical and ideal in thedesign of a treatment including the possibilities of newprevention and management algorithms [20] Type 1 CRSreflects rapid worsening of cardiac function leading to acutekidney injury Type 2 CRS comprises chronic abnormalitiesin cardiac function leading to progressive chronic kidneydisease Type 3 CRS consists of an abrupt worsening ofrenal function causing acute cardiac dysfunction Type 4 CRSdescribes primary chronic kidney disease causing decreasedcardiac function ventricular hypertrophy diastolic dysfunc-tion andor an increased risk of adverse cardiovascularevents Type 5 CRS reflects the presence of combined cardiacand renal dysfunction due to acute or chronic systemicdisorders [20 21]

3 Cardiorenal MetabolicSyndrome Pathophysiology

The pathophysiology of cardiorenal syndrome involves inter-related hemodynamic and neurohormonal mechanismsincluding sympathetic overactivity the renin-angiotensin-aldosterone system various chemical mediators (nitric oxideprostaglandins endothelins etc) and oxidative stress [1722] Traditionally CRS is characterized by an impairment ofkidney function caused by hypoperfusion and cardiac pumpfunction failure [23 24] The bidirectional interplay betweenthe heart and the kidneys and the impact of numerousother factors on this interaction have been shown to befundamental in the pathogenesis of CRS [20] (Figure 1)However the detailed mechanisms underlying the interplayof CRS still have not been completely delineated [5]

31 DirectHemodynamicMechanisms Theheart and kidneyshave been known to share responsibility for maintaining

hemodynamic stability through a tight-knit relationship thatcontrols cardiac output volume status and vascular tone [25]CRS is initiated by left ventricular systolic dysfunction whichleads to decreased renal blow flow followed by activation offluid retention mechanisms This subsequently causes wors-ening of cardiac pumping capacity resulting in initiating avicious cycle and eventual organ deterioration [11] Howeverthe simple hemodynamic variations are only a part of thecomplex pathophysiology of CRS [1 20] The pathophysiol-ogy of kidney dysfunction in the context of heart diseaseis much more complex than a simple reduction of cardiacoutput [5] Several other mechanisms are involved and couldpotentially be considered as a basis for the therapeutic man-agement of this syndrome [20] The pathophysiology of thecardiorenal syndrome involves interrelated hemodynamicand neurohormonal mechanisms including the sympatheticnervous system (SNS) the renin-angiotensin-aldosteronesystem (RAAS) and endothelin and arginine vasopressinsystem activation [22] Moreover neurohormones are strongprecipitants and are also mediators of an oxidative injurycascade that can lead to widespread endothelial dysfunctioninflammation and cell death in the CRS [11]

32 Autonomic Nervous System The adverse consequencesof sympathetic hyperactivity are one of the harmful compen-satory mechanisms that occur in CRS [11] Sustained elevatedadrenergic tone causes a reduction in 120573-adrenergic receptordensity particularly 120573

1 within the ventricular myocardium

as well as uncoupling of the receptor from the intracellularsignallingmechanisms [26] Less well appreciated are the sys-temic effects of renal sympathetic stimulation [11] Howeverincreased kidney sympathetic activation and catecholaminerelease in the setting of reduced catecholamine clearance withan already impaired kidney function are a part of the self-deteriorating cycle that aggravates kidney dysfunction andheart failure [27]

33 The Renin-Angiotensin-Aldosterone System The CRSoccurs with both hypoperfusion associated with decreasedcardiac output and venous congestion [25] Downregulationof renal perfusion stimulates renin secretion which in turnactivates the RAAS followed by activation of the SNS [28]The extreme sodium avidity and ventricular remodelingconferred by RAAS elaboration in heart failure are a mal-adaptive response to altered haemodynamics sympatheticsignalling and progressive renal dysfunction [11] One of thedeleterious actions of the RAAS in the CRS is the activationof nicotinamide adenine dinucleotide phosphate (NADPH)oxidase by angiotensin II (Ang II) resulting in formation ofreactive oxygen species (ROS) [29] Ang II potentially actingthrough changes in the cellular redox status is implicated invascular inflammation via the nuclear factor kappaB (NF-120581B)pathway which induces production of adhesion molecules[30 31] Angiotensin-converting enzyme (ACE) inhibitionand aldosterone antagonism have shown a beneficial effect incardiac failure by inhibiting the intracardiac RAAS reductionin adrenergic tone improvement in endothelial functionand prevention of myocardial fibrosis [32] Moreover ACE

Journal of Diabetes Research 3

uarr Sympathetic hyperactivity

uarr Renin-angiotensin system activity

uarr Oxidative stressuarr Angiotensin II production

uarr After loadRenal efferentuarr pressure darr Cardiac output

darr Renal blood flowdarr GFR

Kidney failure

uarr Vasoconstriction

uarr Sodiumretention

Heart failureAnemia

uarr Apoptosis fibrosis

uarr Adenosine

uarr Arginine vasopressin

Figure 1 Schematic representation showing the pathophysiological interaction between heart and kidney in CRS and potential sitesof intervention by herbal and traditional natural medicine (adapted from [11]) Red arrows indicate the direction of effects of knownphytotherapeutic agents

inhibitors and angiotensin receptor blockers have importantrenoprotective effects in hypertensive patients with nondia-betic renal disease and individuals with diabetic nephropathy[33]

34 Endothelial Dysfunction Endothelial dysfunction is oneof the major contributors to abnormal vasomotor activityin patients with heart failure [34] Nitric oxide (NO) anendothelium-derived relaxing factor is a major regulatorof vascular tone through its potent vasodilatory effect [35]Therefore deregulation of NO is known to be a majorcontributor to endothelial dysfunction in heart failure [36]In addition the disequilibrium between NO and ROS byincreased ROS production a low antioxidant status andlower availability of NO have been shown to increase activityof preganglionic sympathetic neurons It also stimulatesRAAS directly by damaging the renal tubular or intestinalcells or by afferent vasoconstriction with chronic inhibitionof NO synthesis [37 38]

35 InflammatoryMediators andOxidative Injury Therecur-rent inflammatory state that is present in both chronic kidneydisease and heart failure causes ROS production by activatingleukocytes to release the oxidative contents [39] Ang II hasbeen implicated to be involved in a myriad of inflammatoryand oxidative reactions for instance infusion of Ang IIincreased tumour necrosis factor 120572 (TNF-120572) production inthe kidney increased renal synthesis of interleukin (IL)-6monocyte chemoattractant protein-1 (MCP-1) and elevatedtissue levels of activated of NF-120581B [40] Ang II has also beenshown to stimulate superoxide generation through activationof the NADH oxidase and NADPH oxidase [29] MoreoverSNS activity in both kidney and heart failure has been shownto be induced by inflammation through norepinephrine-mediated cytokine production and by releasing neuropeptide

Y which alters cytokine release and immune cell function [541] Moreover cytokines have been shown to stimulate reninsecretion as a component of the systemic stress responseand tubulointerstitial inflammation has effects on adaptiveresponses of glomerular hemodynamics and impaired renalfunction [42]

36 Arginine Vasopressin Plasma levels of arginine vaso-pressin increase in the setting of heart failure Thus not onlydoes arginine vasopressin cause vasoconstriction throughvasopressin V1 receptors (arteriolar vasoconstriction) anda consequent increase in afterload but it can also producewater retention via vasopressin V2 receptors (free waterreabsorption) which mediate the antidiuretic activity ofarginine vasopressinThis combination of effects additionallymay enliven the haemodynamic vicious cycle of CRS [43 44]

37 Adenosine The autacoid adenosine is known to haveregulatory effects on kidney function through the adeno-sine A1 receptor Elevated plasma levels of adenosine havebeen described in patients with heart failure [45] Increasedadenosine generation has been shown during hypoxia [46]which can occur in patients with heart failure owing tocirculatory compromise Thus adenosine dysregulation canact as a self-deteriorating cycle synergistically compoundingthe pathophysiology of CRS

38 Cardiorenal-Anaemia Syndrome Anaemia is common inindividuals with chronic kidney and heart disease and hasbeen shown to contribute to an abnormal renal oxidative state[47 48] Moreover it has been shown that severe anaemiacould be a causative factor for cardiac and renal disease inpatients without previous basic heart disease [39] Tissuehypoxia as a consequence of anaemia leads to peripheralvasodilatation and decreased vascular resistance which in


turn reduces blood pressure The SNS is then activatedcausing renal vasoconstriction followed by downregulationof renal blow flow glomerular filtration rate (GFR) andeventual renal ischemia [49] The reduced renal blood flowactivates the RAAS causing further vasoconstriction andsalt and fluid retention This fluid retention causes leftventricular hypertrophy leading to necrosis and apoptosisof myocardial cells myocardial fibrosis and cardiomyopathyresulting in heart failure [50 51] Anaemia is postulated as acontributor to decreased shear stress leading to deterioratingcardiac and renal function by various mechanisms includinga direct effect of worsening hemodynamic compromise andendothelial dysfunction [52 53] Therefore anaemia has amajor role in the pathogenesis of CRS [20]

4 Cardiorenal Syndrome in Diabetes

All forms of diabetes are characterized by chronic hyper-glycemia and the development of diabetes-specific microvas-cular pathology in the renal glomerulus causing nephropathy[54] Diabetes is also associated with accelerated atheroscle-rotic macrovascular disease affecting arteries that supply theheart resulting in coronary heart disease stroke peripheralarterial disease cardiomyopathy and myocardial infarction[54 55] In diabetes the kidney is involved through progres-sive sclerosisfibrosis and proteinuria due to the overactivityof the transforming growth factor-beta (TGF-120573) systemand the vascular endothelial growth factor (VEGF) system[56] CRS in diabetes refers to pathophysiological conditionswhere the heart and the kidneys are simultaneously affectedby a systemic disorder leading to injury andor dysfunctionof both organ systems [56]

41 Diabetic Nephropathy in Cardiorenal Syndrome Diabetesis a well-established risk factor for cardiovascular diseaseand a significant proportion of diabetic patients progressivelydevelops clinically significant nephropathy [56] Diabeticnephropathy (DN) is one of the major complications ofdiabetes and a major cause of end stage renal disease inmost countries [57ndash59] More than 30 of diabetic patientsdevelop clinically evident DN 10 to 20 years from the onset ofdiabetes mellitus with a 10ndash30 increase in treatment costs[60] DN is characterized by excessive amassing of extracellu-lar matrix (ECM) with thickening of glomerular and tubularbasement membranes and increased amounts of mesangialmatrix which ultimately progress to glomerulosclerosis andtubule-interstitial fibrosis [61] Persistent hyperglycemia alsoactivates vasoactive hormonal pathways including the RAASand endothelin These in turn activate second messengersignaling pathways such as protein kinase C (PKC) andMAP kinase (MAPK) and transcription factors such as NF-120581B that lead to the alteration in gene expression of growthfactors and cytokines such as TGF-120573 [62 63] The financialcost of dialysis and the costs of renal transplantation arefiscally prohibitive for patients and health-care systems [64]Current therapy of DN includes dietary protein restrictionblood pressure control ACE inhibitors and angiotensinreceptor blockers [65] However large numbers of patients

still develop intractable diseaseThis has prompted significantbasic and clinical interest in the use of traditional medicinesfor the treatment of DN [66] Moreover these medicines maypotentially reverse kidney damage at the onset of proteinuriaHowever little is known about the renoprotective effects ofherbal medicines [64]

42 Diabetic Cardiomyopathy in Cardiorenal Syndrome Dia-betic patients have been shown to suffer high mortalityrates with cardiovascular disease being the major cause ofdeath accounting for some 50 of all diabetes fatalities [56]Various studies have shown that the risk for cardiovascularevents increases by two- to fourfold in patients with type2 diabetes [67] Moreover studies have shown that diabeticpatients without previous myocardial infarction have as higha risk of myocardial infarction as nondiabetic patients withprevious myocardial infarction [68] The poor prognosis indiabetic patients with ischemic heart disease has been shownto enhance myocardial dysfunction leading to acceleratedheart failure (diabetic cardiomyopathy) [69ndash71] Diabeticcardiomyopathy (DC) is characterized by excessive lipidaccumulation with increased triacylglycerol (TAG) storesand fibrosis in the left ventricle The known pathogenicmechanisms of DC are metabolic disturbance (depletion ofglucose transporter 4 increased free fatty acids carnitinedeficiency and changes in calcium homeostasis) myocardialfibrosis (associated with increase in Ang II IGF-I andinflammatory cytokines) small vessel disease (microan-giopathy impaired coronary flow reserve and endothelialdysfunction) cardiac autonomic neuropathy (denervationand alterations in myocardial catecholamine levels) andinsulin resistance (hyperinsulinemia and reduced insulinsensitivity) [72] However all the potential mechanisms havenot been completely delineated and no specific treatmentcombination is presently defined [73] Therefore the useof herbal medicine as a therapeutic modality in improvingcardiovascular risk has warranted further attention fromseveral researchers [74]

43 Proteinuria and Cardiorenal Syndrome Microalbumin-uria is a common complication of diabetes and has beena strong predictor of subsequent development of overt DN[75 76] Moreover microalbuminuria is also associated withan increased risk of cardiovascular events and mortality[77] Studies have shown that diabetic patients with microal-buminuria or proteinuria have a 2ndash10 times more rapidprogression of coronary heart disease vascular diseases andarteriosclerosis [78 79] In patients with heart failure andrenal dysfunction a new treatment focus has been suggestedto first recognize the CRS and treat the whole patient in thelong term by optimizing the heart failure therapy while alsopreserving renal function [56]

5 Current Conventional Therapies(Orthodox Medicine)

Orthodox therapeutic management of CRS focuses mainlyon correcting hemodynamic abnormalities However such


an approach is complex and prone to treatment refractorinessandor worsening dysregulation of one component (eg kid-ney function) by targeting another component (eg volumeoverload) [20] Although clinical guidelines for managingboth heart and kidney diseases have been published untilnow agreed-on evidence based clinical treatment guidelinesfor patients with CRS are lacking [80] Moreover withthe development of resistance to many standard conven-tional therapies such as diuretics and inotropes there is anincreasing interest in developing novel therapies to optimizetreatment [17]

6 Herbal and Traditional Medicines andCardiorenal Syndrome

In recent years there has been growing attention to alterna-tive therapies and the therapeutic use of plant-origin naturalproducts [14] Herbal medicines have gained significantimportance in the last few decades and the demand for useof natural products in the management of cardiovascularand renal diseases [81 82] Despite modern pharmacother-apeutics and advancement in an ever-changing world ofbiotechnology a lack of understanding still exists with regardto the bioactivity of many phytotherapeutic medicines [83]This has prompted research to understand the mechanismof action of natural medicines and seek new products forbetter management of cardiovascular and renal diseasesThis section summarizes the current research on variousherbal and traditional medicines capable of modulating CRSpathogenesis (Table 1)

61 Traditional Chinese Medicines Apocynum venetum(Dogbane) traditionally used to calm the liver soothethe nerves dissipate heat and promote diuresis hasshown protective effects on renal function of kidneysof streptozotocin-induced diabetic rats through themodulation of the renal cortexrsquos superoxide dismutase (SOD)and glutathione (GSH) activities [84] Moreover Apocynumvenetum has shown cardiotonic effects through the inhibitionof phosphodiesterase 3 (PDE-3) [85] In addition Apocynumvenetum has also been shown to protect cardiac function inthe process of ischemia reperfusion through the mechanismof improving energy metabolism scavenging oxygen freeradicals and inhibiting the production of free radicals in theischemic myocardium [87]

Astragalus membranaceus (Astragalus) is a traditionalherb used for thousands of years in China and East Asiafor kidney disease [118] Astragalus injection has shown arenal protective effect (ie BUN SCr CCr and urine protein)and systemic state improvement (serum albumin level)This study has suggested that although there are unknownbioactive ingredients and an undefined mechanism of renalprotection the role of Astragalus in the treatment of DNmaybe of clinical significance [119] Moreover another experi-mental study has shown that Astragalus membranaceus rootis effective in reducing fasting blood glucose and albuminurialevels in reversing the glomerular hyperfiltration state andin ameliorating the pathological changes of early DN in rat

models [86] Different fractional components isolated fromAstragalusmembranaceus have been shown to protect cardiacfunction in the process of ischemia reperfusion through themechanisms of improving energy metabolism scavengingoxygen free radicals and inhibiting the production of freeradicals in the ischemic myocardium [87]

The extract of Ginkgo biloba (Ginkgo) leaf has shownprotective action on earlyDN through significantly decreasedurinary microalbumin (mALB) alpha1-microglobulin(alpha1-MG) immunoglobulin (IgG) transferrin (TF)retinal binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) [88] Ginkgo biloba extract injectionhas also been shown to be effective in treating earlyDN through decreasing urinary albumin excretion rateregulating blood lipids improving renal function andhemorheology [89] Further study has explored the effectof ginkgo leaf extract on vascular endothelial functionin patients with early stage DN Ginkgo leaf extract hasbeen shown to decrease the plasma concentration of VonWillebrand factor (vWF) raise the plasma NO level andimprove the endothelium dependent vascular dilatingfunction in DN patients [90] Moreover extract of Gingkobiloba has been shown to decrease the amounts of serumsoluble intercellular cell adhesion molecule-1 (ICAM-1)and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with early DN [91] In addition relevantclinical trials with Ginkgo biloba leaves are being carriedout particularly in the treatment of arterial and venousinsufficiency and in the prevention of thrombosis Howeverthe future study of potential benefits of Ginkgo biloba incardiovascular diseases warrants more rigorous systematicinvestigation of its cardiovascular properties [92]

The root of Salvia miltiorrhiza commonly known asdanshen is traditionally used for treating cardiovascularand inflammatory diseases in East Asian countries [120]Investigations have shown that Salvia miltiorrhiza inhibitsthe progression of DN by modulating high levels of 24 hurinary protein excretion the serum and kidney levelsTGF-120573

1 the kidney concentrations of collagen IV mono-

cytesmacrophages (ED-1) and the receptor for advancedglycation end-products (RAGE) [93] Roots of Salvia miltior-rhizahave shownprotective effects against hypobaric hypoxiathrough modulation of hypoxia-induced tachycardia con-centration ofmalonyldialdehyde [94] lipid peroxidase (LPO)and SOD [95] In addition danshen has been shown toincrease endothelial-dependent vasorelaxation and displayedvasoprotection in ovariectomized (OVX) rats fed with highfat diet primarily by stimulating NO production upregu-lating the mRNA expression of endothelial NO synthaseand downregulating themRNA expression of TNF-120572 ICAM-1 and VACM-1 in isolated aortas These findings indicatethat Salviamiltiorrhiza is potentially beneficial for preventingcardiovascular disease [96]

Cordyceps sinensis (Cordyceps Mushroom) is a valuedtonic herb to treat a wide range of disorders including respi-ratory renal liver and cardiovascular diseases low libido andimpotence and hyperlipidemia [97] Cordyceps sinensis hasbeen shown to ameliorate glomerular sclerosis by reducingproteinuria decreasing the expressions of fibronectin (FN)


Table 1 Modern research on natural medicines capable of modulating cardiorenal syndrome related pathogenesis

Herbal medicines Functions ReferencesApocynum venetum(Dogbane)

Modulating effect on SOD and GSH activities Improving energy metabolismscavenging oxygen free radicals and inhibition of PDE-3 [84 85]

Astragalus membranaceus(Astragalus)

Modulating effect on BUN SCr CCr urine protein and serum albumin levelsReducing fasting blood glucose albuminuria levels and reversing the glomerularhyperfiltration state

[86 87]

Ginkgo biloba (Ginkgo)Downregulating the levels of urinary mALB alpha1-MG IgG TF RBP and NAGDecreasing the levels of vWF ICAM-1 and VCAM-1 Raise the plasma NO leveland improve the endothelium dependent vascular dilating function

[88ndash92]

Root of Salviamiltiorrhiza (Danshen)

Modulating effect on levels of TGF-1205731 collagen IV ED-1 RAGE malondialdehydeLPO and SOD Upregulating the level of endothelial NO synthase anddownregulating the levels of TNF-120572 ICAM-1 and VACM-1

[93ndash96]

Cordyceps sinensis(CordycepsMushroom)

Decreasing the levels of FN collagen-IV CTGF and PAI-1 and proteinuria andincreasing the level of MMP-2 [97ndash99]

Trigonella foenum-graecum (Fenugreek)

Increasing concentrations of malondialdehyde and level of8-hydroxy-21015840-deoxyguanosine Decreasing the levels of LPO and increasing thelevels of CAT GST and GSH

[100ndash102]

Terminalia arjuna stembark (Arjuna)

Downregulation in LPO Upregulating the levels of SOD catalase GSH peroxidaseGST GSH reductase and glucose-6-phosphate dehydrogenase GSH and total TSHand NPSH

[103 104]

Salacia oblonga(Ekanayaka) Suppressing angiotensin IIAT1 signaling and overexpression of TGF-1205731 and 1205732 [105ndash107]

Curcumin from Curcumalonga (Turmeric)

Antagonizing TNF-120572-mediated decrease in PPAR-120574 and blocked transactivation ofNF-120581B and repression of PPAR-120574 Attenuating myocardial dysfunction throughAktGSK-3120573 signaling pathway

[108 109]

Crataegus oxyacantha Linn(Hawthorn)

Attenuating apoptotic incidence by regulating Akt and HIF-1 signaling pathwaysSignificant attenuation of phosphatase and tensin homolog deleted on chromosome10 and upregulation of phospho-Akt and c-Raf levels ACE inhibiting effect

[110 111]

Mangiferin fromMangiferaindica L (Mango)

Inhibition of glomerular ECM expansion and the levels of TGF-1205731 and collagen IVDecrease in glycosylated hemoglobin and CPK levels [112 113]

Silymarin from Silybummarianum (Milk Thistle)

Downregulating the levels of malondialdehyde NO and protein carbonylSuppression of the neutrophil infiltration and preventing the fall in mean arterialpressure and HR during ischemia-reperfusion

[114 115]

Panax quinquefolius(North American ginseng)

Downregulating the levels of NF-120581B (p65) ECM proteins vasoactive factors andFas Upregulating the level of Bcl-2 [116 117]

collagen-IV connective tissue growth factor (CTGF) andplasminogen activator inhibitor 1 (PAI-1) and increasingthe expression of matrix metalloproteinase-2 (MMP-2) [98]Further study has shown that Cordyceps sinensis affordscardioprotection by reduced postischemic diastolic dysfunc-tion and improved recovery of pressure development andcoronary flow Moreover this study has also suggested thatpreischemic adenosine receptor activation may be involvedin reducing contracture in hearts pretreated with Cordycepssinensis [99]

62 Ayurvedic Medicines Trigonella foenum-graecum (Fenu-greek) has been reported to possess antidiabetic and antiox-idative effects Trigonella foenum-graecum seed aqueousextract has been shown to restore the kidney function of dia-betic rats through decreased activities of SOD and catalaseincrease concentrations ofmalondialdehyde in the serumandkidney and increase levels of 8-hydroxy-21015840-deoxyguanosinein urine and renal cortex DNA Furthermore all of theultramorphologic abnormalities in the kidney of diabetic

rats including the uneven thickening of the glomerular basemembrane have been shown to ameliorate by Trigonellafoenum-graecum treatment [100] Trigonella foenum-graecumalso has shown a significant decrease in LPO increase inthe activities of key antioxidant enzymes such as SODcatalase and glutathione-s-transferase (GST) and reducedGSH contents in heart tissue of diabetic rats [101 102]

Terminalia arjuna (Arjuna) bark an indigenous plantused in Ayurvedic medicine in India primarily as a car-diotonic is also used in treating diabetes anaemia tumorsand hypertension [121] The ethanolic extract of Terminaliaarjuna stem bark has shown significant reduction in LPOincrease in SOD catalase glutathione peroxidase GST glu-tathione reductase and glucose-6-phosphate dehydrogenasereduced glutathione vitamin A vitamin C vitamin E totalsulfhydryl groups (TSH) and nonprotein sulfhydryl groups(NPSH) in kidney of alloxan-induced diabetic rats [103]Moreover Terminalia arjuna bark extract has shown a sig-nificant prophylactic and therapeutic beneficial effect on pro-tection of heart against isoproterenol-induced chronic heart


failure possibly through maintaining endogenous antioxi-dant enzyme activities and inhibiting LPOand cytokine levels[104]

Salacia oblonga (Ekanayaka) root has been used in thetreatment of diabetes and obesity in the Ayurvedic systemof Indian traditional medicine [105] One recent study hasshown that SO root attenuates diabetic renal fibrosis atleast in part by suppressing angiotensin IIAT1 signaling[106] Chronic administration of Salacia oblonga extracthas been shown to improve interstitial and perivascularfibrosis through suppression of the overexpression ofmRNAsencoding TGF-120573

1and 120573

2in the obese Zucker rat heart [107]

Research over the last two decades has revealed thatcurcumin one of the active components of Curcuma longa(Turmeric) can reverse insulin resistance hyperglycemiahyperlipidemia and other symptoms linked to obesityand obesity-related metabolic diseases [122] Curcumin hasshown protective effects against chronic renal failure byantagonizing TNF-120572-mediated decrease in PPAR-120574 andblocked transactivation of NF-120581B and repression of PPAR-120574The results have indicated that the anti-inflammatory prop-erty of curcumin may be responsible for alleviating chronicrenal failure in nephrectomy (Nx) animals [108] One furtherstudy has suggested that curcumin has beneficial effect inthe treatment of DC and other cardiovascular disorders byattenuating myocardial dysfunction cardiac fibrosis AGEsaccumulation oxidative stress inflammation and apoptosisin the heart of diabetic rats Moreover AktGSK-3120573 signalingpathway may be involved in mediating these effects [109]

63 Western Herbal Medicines Crataegus oxyacantha Linncommonly known as Hawthorn is one of the most widelyused herbal heart tonics [123] Crataegus oxyacantha admin-istration has shown a significant attenuation of phosphataseand tensin homolog deleted on chromosome 10 and upreg-ulation of phospho-Akt and c-Raf levels in the heart Thisstudy has suggested that Crataegus oxyacantha extract atten-uates apoptotic incidence in the experimental myocardialischemia-reperfusion model by regulating Akt and hypoxia-inducible factor (HIF-1) signaling pathways [110] MoreoverCrataegus oxyacantha has also shown ACE inhibition [111]

Mangiferin one of the main components of Mangiferaindica L (Mango) has been known as a useful cardio-protective agent by reducing oxidative damage [124] Thestudy has shown that mangiferin inhibits glomerular extra-cellular matrix expansion and accumulation and TGF-120573

1

overexpression in glomeruli of DN rats Mangiferin wasalso observed to inhibit the proliferation in high glucoseinduced-mesangial cells and the overexpression of collagentype IV in AGEs induced-mesangial cells [112] Moreoverintraperitoneal administration ofmangiferin has been shownto exhibit significant decrease in glycosylated haemoglobinand CPK levels along with the amelioration of STZ-inducedoxidative damage in cardiac tissue and renal tissue [113]

Silymarin one of the active components of Silybummarianum (Milk thistle) is a known antioxidant hepato-protectant and anti-inflammatory agent with antibacterialantiallergic antiviral and antineoplastic properties [125]

Silymarin has been shown to protect the kidneys against IRinjury through downregulation of increased serum and tissuemalondialdehyde NO and protein carbonyl [114] One studyhas suggested that silymarin has cardioprotective activityagainst ischemia-reperfusion induced myocardial infarctionin rats Moreover suppression of the neutrophil infiltrationand prevention of the fall in mean arterial pressure and HRduring ischemia-reperfusion further support the protectionoffered by silymarin against ischemia reperfusion injury [115]

Panax quinquefolius (North American ginseng) has tradi-tionally been known to be effective on the endocrine cardio-vascular immune and central nervous systems [126] Panaxquinquefolius has shown a preventive effect on DN throughdownregulation of oxidative stress NF-120581B (p65) levels ECMproteins and vasoactive factors [116] In addition the effectof Folium Panax quinquefolius saponins was conducted onapoptosis of cardiac muscle cells and apoptosis-related geneexpression in rats with acute myocardial infarction Thisstudy has shown that Folium Panax quinquefolius saponinsinhibits cardiac muscle cell apoptosis downregulates Fasprotein expression upregulates Bcl-2 protein expression andhas antagonistic effect in myocardial ischemic injury [117]

64 Herbal Toxicology and Safety Nephropathy Althoughthe use of Chinese herbal products is increasing scientificevidence on the safety efficacy quality and regulatory controldoes not always support such popularity [127] Some herbaland traditional medicinescontaining aristolochic acid areknown to be nephrotoxic and carcinogenic [128] Aris-tolochic acid nephropathy (AAN) is characterized by pro-gressive fibrosing interstitial nephritis leading to end-stagerenal disease urothelial malignancy and severe anaemia[129] Although botanicals known or suspected to containaristolochic acidwere no longer permitted inmany countriesseveral AAN cases were regularly observed all around theworld [130] Moreover medicinal herbal extracts may exertrenal toxicity through their inherent properties making itimportant to continue compiling information regarding thepotential toxicity of all medicinal herbs [131] The toxicologyand safety of flavonoids prepared using local available botan-icals also demonstrated cases of acute renal failure after useof Taxus celebica ciandidaol and Cupresssus funebris [132]Toxicological effects of herbal use could also have potentialdetrimental effects on the CRS and this also needs to beresearched and characterized clinically and mechanistically

7 Conclusion

The association between kidney failure and cardiovasculardiseases has been shown repeatedly particularly in the pastdecade [133ndash135] CRS is an interdependent involvementof both the heart and the kidney which can progress ina spiraling fashion leading to volume overload diureticresistance and further involvement of all organ systems inwhich the clinical condition will likely worsen and multi-organ system failure can ensue [5] Moreover clinical trialshave shown that deterioration of renal function decreasesafter the first myocardial infarction particularly in patients


who already had impairment of renal function [136 137]The heterogeneous and complex pathophysiology of CRSmakes patient management an intricate clinical challenge[22] Although clinical guidelines for managing both heartfailure and chronic renal disease have been drawn until nowagreed-upon guidelines surrounding the therapy of patientswith CRS are lacking Therefore future treatment directionsshould take into consideration both kidney and heart func-tion [80] The current orthodox pharmaceutical treatmentssuch as diuretics vasodilators or inotropes could cause areduction in plasma volume renal perfusion redistributionwith cortical vasoconstriction decrease in preload with anincrease in venous congestion and further neurohormonalactivation leading to a worsening outcome [80] Moreoverthe increasing importance of understanding the specificmolecular and biochemical changes in CRS emphasizes therequirement for development of novel therapeutic interven-tions Herbal medicine has a long and respected history andholds a valuable place in the treatment of cardiovascular andkidney diseases [138 139] This review confirms that naturaland traditional herbal medicines have potential as alternativeor combination (complementary) therapy for CRS Despitethe long history of herbal and natural traditional medicinesfor the management of CRS there is still no conclusive evi-dence for their effectiveness or their safety profilesThereforefurther investigation into their exact mechanisms of actionare warranted and required to gather proof of efficacy andsafety for possible protection against CRS-related pathophys-iology and disease progression

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] L G Bongartz B Braam C A Gaillard et al ldquoTarget organcross talk in cardiorenal syndrome animal modelsrdquo AmericanJournal of Physiology Renal Physiology vol 303 pp F1253ndashF1263 2012

[2] N S Anavekar J J VMcMurray E J Velazquez et al ldquoRelationbetween renal dysfunction and cardiovascular outcomes aftermyocardial infarctionrdquo New England Journal of Medicine vol351 no 13 pp 1285ndash1295 2004

[3] K Damman G Navis A A Voors et al ldquoWorsening renalfunction and prognosis in heart failure systematic review andmeta-analysisrdquo Journal of Cardiac Failure vol 13 no 8 pp 599ndash608 2007

[4] H L Hillege A R J Girbes P J de Kam et al ldquoRenalfunction neurohormonal activation and survival in patientswith chronic heart failurerdquo Circulation vol 102 no 2 pp 203ndash210 2000

[5] H S Mahapatra R Lalmalsawma N P Singh M Kumar andS C Tiwari ldquoCardiorenal syndromerdquo Iranian Journal of KidneyDiseases vol 3 no 2 pp 61ndash70 2009

[6] J D Harnett R N Foley G M Kent P E Barre D Murrayand P S Parfrey ldquoCongestive heart failure in dialysis patientsprevalence incidence prognosis and risk factorsrdquo Kidney Inter-national vol 47 no 3 pp 884ndash890 1995

[7] F A McAlister J Ezekowitz M Tonelli and P W ArmstrongldquoRenal insufficiency and heart failure prognostic and therapeu-tic implications from a prospective cohort studyrdquo Circulationvol 109 no 8 pp 1004ndash1009 2004

[8] C Ronco P McCullough S D Anker et al ldquoCardio-renalsyndromes report from the consensus conference of the acutedialysis quality initiativerdquo European Heart Journal vol 31 no 6pp 703ndash711 2010

[9] C Lazzeri S Valente R Tarquini and G F Gensini ldquoCardiore-nal syndrome caused by heart failure with preserved ejectionfractionrdquo International Journal of Nephrology vol 2011 ArticleID 634903 7 pages 2011

[10] D E Forman J Butler Y Wang et al ldquoIncidence predictorsat admission and impact of worsening renal function amongpatients hospitalized with heart failurerdquo Journal of the AmericanCollege of Cardiology vol 43 no 1 pp 61ndash67 2004

[11] J S Bock and S S Gottlieb ldquoCardiorenal syndrome newperspectivesrdquo Circulation vol 121 no 23 pp 2592ndash2600 2010

[12] C W Yancy M Lopatin L W Stevenson T De Marco andG C Fonarow ldquoClinical presentation management and in-hospital outcomes of patients admitted with acute decompen-sated heart failure with preserved systolic function a reportfrom theAcuteDecompensatedHeart FailureNational Registry(ADHERE) Databaserdquo Journal of the American College ofCardiology vol 47 pp 76ndash84 2006

[13] L W Stevenson A Nohria and L Mielniczuk ldquoTorrent ortorment from the tubulesrdquo Journal of the American College ofCardiology vol 45 no 12 pp 2004ndash2007 2005

[14] D-D Li J-H Chen Q Chen et al ldquoSwietenia mahagonyextract shows agonistic activity to PPAR120574 and gives ameliorativeeffects on diabetic dbdbmicerdquoActa Pharmacologica Sinica vol26 no 2 pp 220ndash222 2005

[15] M K Song B D Roufogalis and T HW Huang ldquoModulationof diabetic retinopathy pathophysiology by natural medicinesthroughPPAR-120574-related pharmacologyrdquoBritish Journal of Phar-macology vol 165 no 1 pp 4ndash19 2012

[16] M Sarraf A Masoumi and R W Schrier ldquoCardiorenal syn-drome in acute decompensated heart failurerdquo Clinical Journalof the American Society of Nephrology vol 4 no 12 pp 2013ndash2026 2009

[17] N Pokhrel NMaharjan B Dhakal andR R Arora ldquoCardiore-nal syndrome a literature reviewrdquo Experimental and ClinicalCardiology vol 13 no 4 pp 165ndash170 2008

[18] C Ronco M Cicoira and P A McCullough ldquoCardiorenalsyndrome type 1 pathophysiological crosstalk leading to com-bined heart and kidney dysfunction in the setting of acutelydecompensated heart failurerdquo Journal of the American Collegeof Cardiology vol 60 pp 1031ndash1042 2012

[19] C Ronco and M Cozzolino ldquoMineral metabolism abnor-malities and vitamin D receptor activation in cardiorenalsyndromesrdquo Heart Failure Reviews vol 17 pp 211ndash220 2012

[20] P Hatamizadeh G C FonarowM J Budoff et al ldquoCardiorenalsyndrome pathophysiology and potential targets for clinicalmanagementrdquo Nature Reviews Nephrology vol 9 pp 99ndash1112013

[21] C Ronco A A House andMHaapio ldquoCardiorenal syndromerefining the definition of a complex symbiosis gone wrongrdquoIntensive Care Medicine vol 34 no 5 pp 957ndash962 2008

[22] M S Ahmed C F Wong and P Pai ldquoCardiorenal syndromemdasha new classification and current evidence on its managementrdquoClinical Nephrology vol 74 no 4 pp 245ndash257 2010


[23] K V Liang A W Williams E L Greene and M M RedfieldldquoAcute decompensated heart failure and the cardiorenal syn-dromerdquo Critical CareMedicine vol 36 no 1 pp S75ndashS88 2008

[24] C Ronco M Haapio A A House N Anavekar and RBellomo ldquoCardiorenal syndromerdquo Journal of the AmericanCollege of Cardiology vol 52 no 19 pp 1527ndash1539 2008

[25] G Viswanathan and S Gilbert ldquoThe cardiorenal syndromemaking the connectionrdquo International Journal of Nephrologyvol 2011 Article ID 283137 10 pages 2011

[26] M R Bristow ldquoTreatment of chronic heart failure with 120573-adrenergic receptor antagonists a convergence of receptorpharmacology and clinical cardiologyrdquo Circulation Researchvol 109 no 10 pp 1176ndash1194 2011

[27] K Laederach and P Weidmann ldquoPlasma and urinary cat-echolamines as related to renal function in manrdquo KidneyInternational vol 31 no 1 pp 107ndash111 1987

[28] I A Reid ldquoInteractions between ANG II sympathetic ner-vous system and baroreceptor reflexes in regulation of bloodpressurerdquo American Journal of Physiology Endocrinology andMetabolism vol 262 no 6 pp E763ndashE778 1992

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[30] M Ruiz-Ortega O Lorenzo and J Egido ldquoAngiotensin IIIincreases MCP-1 and activates NF-120581B and AP-1 in culturedmesangial andmononuclear cellsrdquo Kidney International vol 57no 6 pp 2285ndash2298 2000

[31] M E PueyoWGonzalez ANicoletti F Savoie J-F Arnal andJ-B Michel ldquoAngiotensin II stimulates endothelial vascular celladhesion molecule-1 via nuclear factor-120581B activation inducedby intracellular oxidative stressrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 20 no 3 pp 645ndash651 2000

[32] G Remuzzi N Perico M Macia and P Ruggenenti ldquoThe roleof renin-angiotensin-aldosterone system in the progression ofchronic kidney diseaserdquo Kidney International vol 68 no 99pp S57ndashS65 2005

[33] A B Lewis and M Chabot ldquoThe effect of treatment withangiotensin-converting enzyme inhibitors on survival of pedi-atric patients with dilated cardiomyopathyrdquo Pediatric Cardiol-ogy vol 14 no 1 pp 9ndash12 1993

[34] R Ferrari T Bachetti L Agnoletti L Comini and S CurelloldquoEndothelial function and dysfunction in heart failurerdquo Euro-pean Heart Journal vol 19 pp G41ndashG47 1998

[35] A J Kanai H C Strauss G A Truskey A L Crews S Grun-feld and T Malinski ldquoShear stress induces ATP-independenttransient nitric oxide release from vascular endothelial cellsmeasured directly with a porphyrinic microsensorrdquo CirculationResearch vol 77 no 2 pp 284ndash293 1995

[36] M Ontkean R Gay and B Greenberg ldquoDiminishedendothelium-derived relaxing factor activity in an experimentalmodel of chronic heart failurerdquo Circulation Research vol 69no 4 pp 1088ndash1096 1991

[37] W C Faquin T J Schneider and M A Goldberg ldquoEffectof inflammatory cytokines on hypoxia-induced erythropoietinproductionrdquo Blood vol 79 no 8 pp 1987ndash1994 1992

[38] M Katoh K Egashira M Usui et al ldquoCardiac angiotensin IIreceptors are upregulated by long-term inhibition of nitric oxidesynthesis in ratsrdquoCirculationResearch vol 83 no 7 pp 743ndash7511998

[39] G M Felker K F Adams Jr W A Gattis and C M OrsquoConnorldquoAnemia as a risk factor and therapeutic target in heart failurerdquoJournal of the American College of Cardiology vol 44 no 5 pp959ndash966 2004

[40] M Ruiz-Ortega M Ruperez O Lorenzo et al ldquoAngiotensinII regulates the synthesis of proinflammatory cytokines andchemokines in the kidneyrdquo Kidney International vol 62 no 82pp S12ndashS22 2002

[41] J Liao J A Keiser W E Scales S L Kunkel and M J KlugerldquoRole of epinephrine in TNF and IL-6 production from isolatedperfused rat liverrdquo American Journal of Physiology RegulatoryIntegrative and Comparative Physiology vol 268 no 4 ppR896ndashR901 1995

[42] L G Sanchez-Lozada E Tapia R J Johnson B Rodrıguez-Iturbe and J Herrera-Acosta ldquoGlomerular hemodynamicchanges associated with arteriolar lesions and tubulointerstitialinflammationrdquo Kidney International vol 64 no 86 pp S9ndashS142003

[43] S R Goldsmith G S Francis and A W Cowley Jr ldquoIncreasedplasma arginine vasopressin levels in patients with congestiveheart failurerdquo Journal of the American College of Cardiology vol1 no 6 pp 1385ndash1390 1983

[44] TMondritzki P KolkhofHN Sabbah et al ldquoDifferentiation ofarginine vasopressin antagonistic effects by selective V2 versusdual V2v1a receptor blockade in a preclinical heart failuremodelrdquo American Journal of Therapeutics vol 18 no 1 pp 31ndash37 2011

[45] H Funaya M Kitakaze K Node T Minamino K KomamuraandM Hori ldquoPlasma adenosine levels increase in patients withchronic heart failurerdquo Circulation vol 95 no 6 pp 1363ndash13651997

[46] V Vallon B Muhlbauer and H Osswald ldquoAdenosine andkidney functionrdquo Physiological Reviews vol 86 no 3 pp 901ndash940 2006

[47] J A Ezekowitz F A McAlister and P W Armstrong ldquoAnemiais common in heart failure and is associated with poor out-comes insights from a cohort of 12 065 patients with new-onsetheart failurerdquo Circulation vol 107 no 2 pp 223ndash225 2003

[48] T BHorwichGC FonarowMAHamiltonWRMacLellanand J Borenstein ldquoAnemia is associated with worse symptomsgreater impairment in functional capacity and a significantincrease in mortality in patients with advanced heart failurerdquoJournal of the American College of Cardiology vol 39 no 11 pp1780ndash1786 2002

[49] G Efstratiadis D Konstantinou I Chytas and G VergoulasldquoCardio-renal anemia syndromerdquoHippokratia vol 12 no 1 pp11ndash16 2008

[50] A M Katz ldquoThe cardiomyopathy of overload an unnaturalgrowth response in the hypertrophied heartrdquo Annals of InternalMedicine vol 121 no 5 pp 363ndash371 1994

[51] D B Johnson and L J DellrsquoItalia ldquoCardiac hypertrophy andfailure in hypertensionrdquo Current Opinion in Nephrology andHypertension vol 5 no 2 pp 186ndash191 1996

[52] I S Anand Y Chandrashekhar R Ferrari P A Poole-Wilsonand P C Harris ldquoPathogenesis of oedema in chronic severeanaemia studies of body water and sodium renal functionhaemodynamic variables and plasma hormonesrdquo British HeartJournal vol 70 no 4 pp 357ndash362 1993

[53] P E Sandgren A M Murray C A Herzog C A Solid D TGilbertson and R N Foley ldquoAnemia and new-onset congestiveheart failure in the general medicare populationrdquo Journal ofCardiac Failure vol 11 no 2 pp 99ndash105 2005


[54] M Brownlee ldquoBiochemistry and molecular cell biology ofdiabetic complicationsrdquo Nature vol 414 no 6865 pp 813ndash8202001

[55] S M Grundy I J Benjamin G L Burke et al ldquoDiabetes andcardiovascular disease a statement for healthcare professionalsfrom the american heart associationrdquo Circulation vol 100 no10 pp 1134ndash1146 1999

[56] H H Karnib and F N Ziyadeh ldquoThe cardiorenal syndrome indiabetes mellitusrdquo Diabetes Research and Clinical Practice vol89 no 3 pp 201ndash208 2010

[57] A Arya S Aggarwal and H N Yadav ldquoPathogenesis ofdiabetic nephropathyrdquo International Journal of Pharmacy andPharmaceutical Sciences vol 2 no 4 pp 24ndash29 2010

[58] A N Lasaridis and P A Sarafidis ldquoDiabetic nephropathy andantihypertensive treatment what are the lessons from clinicaltrialsrdquoAmerican Journal ofHypertension vol 16 no 8 pp 689ndash697 2003

[59] M E Molitch R A de Fronzo M J Franz et al ldquoNephropathyin diabetesrdquo Diabetes Care vol 27 supplement 1 pp S79ndashS832004

[60] X Yin Y Zhang H Wu et al ldquoProtective effects of Astragalussaponin I on early stage of diabetic nephropathy in ratsrdquo Journalof Pharmacological Sciences vol 95 no 2 pp 256ndash266 2004

[61] Y S Kanwar J Wada L Sun et al ldquoDiabetic nephropathymechanisms of renal disease progressionrdquo Experimental Biologyand Medicine vol 233 no 1 pp 4ndash11 2008

[62] C Maric and J E Hall ldquoObesity metabolic syndrome anddiabetic nephropathyrdquoContributions to Nephrology vol 170 pp28ndash35 2011

[63] F N Ziyadeh ldquoMediators of diabetic renal disease the case fortgf-Beta as the major mediatorrdquo Journal of the American Societyof Nephrology vol 15 no 1 pp S55ndashS57 2004

[64] S Shafi N Tabassum and F Ahmed ldquoDiabetic nephropathyand herbal medicinesrdquo International Journal of Phytopharma-cology vol 3 pp 10ndash17 2012

[65] L Yu N A Noble andW A Border ldquoTherapeutic strategies tohalt renal fibrosisrdquo Current Opinion in Pharmacology vol 2 no2 pp 177ndash181 2002

[66] J Xu Z Li M Cao et al ldquoSynergetic effect of Andrographispaniculata polysaccharide on diabetic nephropathy with andro-grapholiderdquo International Journal of Biological Macromoleculesvol 51 pp 738ndash742 2012

[67] J B Buse H N Ginsberg G L Bakris et al ldquoPrimary preven-tion of cardiovascular diseases in people with diabetes mellitusa scientific statement from the AmericanHeart Association andthe American Diabetes Associationrdquo Circulation vol 115 no 1pp 114ndash126 2007

[68] J M M Evans J Wang and A D Morris ldquoComparison ofcardiovascular risk between patients with type 2 diabetes andthose who had had a myocardial infarction cross sectional andcohort studiesrdquo British Medical Journal vol 324 no 7343 pp939ndash942 2002

[69] T J Regan M M Lyons and S S Ahmed ldquoEvidence forcardiomyopathy in familial diabetesmellitusrdquo Journal of ClinicalInvestigation vol 60 no 4 pp 885ndash899 1977

[70] P O Ettinger and T J Regan ldquoCardiac disease in diabetesrdquoPostgraduate Medicine vol 85 no 6 pp 229ndash232 1989

[71] K S Spector ldquoDiabetic cardiomyopathyrdquo Clinical Cardiologyvol 21 no 12 pp 885ndash887 1998

[72] Y F Zhi J B Prins and T H Marwick ldquoDiabetic cardiomy-opathy evidence mechanisms and therapeutic implicationsrdquoEndocrine Reviews vol 25 no 4 pp 543ndash567 2004

[73] F Forcheron A Basset P Abdallah P del Carmine N Gadotand M Beylot ldquoDiabetic cardiomyopathy effects of fenofibrateandmetformin in an experimental model -The Zucker diabeticratrdquo Cardiovascular Diabetology vol 8 article no 16 2009

[74] S Atashak M Peeri M A Azarbayjani S R Stannard and MM Haghighi ldquoObesity-related cardiovascular risk factors afterlong- term resistance training and ginger supplementationrdquoJournal of Sports Science and Medicine vol 10 no 4 pp 685ndash691 2011

[75] R Amin B Widmer A T Prevost et al ldquoRisk of microal-buminuria and progression to macroalbuminuria in a cohortwith childhood onset type 1 diabetes prospective observationalstudyrdquo British Medical Journal vol 336 no 7646 pp 697ndash7012008

[76] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004

[77] H L Hillege V Fidler G F H Diercks et al ldquoUrinary albu-min excretion predicts cardiovascular and noncardiovascularmortality in general populationrdquoCirculation vol 106 no 14 pp1777ndash1782 2002

[78] P Rossing P Hougaard K Borch-Johnsen and H-H ParvingldquoPredictors of mortality in insulin dependent diabetes 10 yearobservational follow up studyrdquo British Medical Journal vol 313no 7060 pp 779ndash784 1996

[79] S F Dinneen and H C Gerstein ldquoThe association of microal-buminuria and mortality in non-insulin-dependent diabetesmellitus a systematic overview of the literaturerdquo Archives ofInternal Medicine vol 157 no 13 pp 1413ndash1418 1997

[80] S Nodari and A Palazzuoli ldquoCurrent treatment in acute andchronic cardio-renal syndromerdquo Heart Failure Reviews vol 16no 6 pp 583ndash594 2011

[81] Z A Mahmood M Sualeh S B Z Mahmood and MA Karim ldquoHerbal treatment for cardiovascular disease theevidence based therapyrdquo Pakistan Journal of PharmaceuticalSciences vol 23 no 1 pp 119ndash124 2010

[82] SMohana Lakshmi TUshaKiranReddy andK SandhyaRanildquoA review on medicinal plants for nephroprotective activityrdquoAsian Journal of Pharmaceutical and Clinical Research vol 5pp 8ndash14 2012

[83] C T Musabayane ldquoThe effects of medicinal plants on renalfunction and blood pressure in diabetes mellitusrdquo Cardiovascu-lar Journal of Africa vol 23 pp 462ndash468 2012

[84] H-Y Chen J-H Wang M Geng et al ldquoProtective effect ofextract of Apocynum venetum on kidneys of streptozotocin-induced diabetic ratsrdquo Yaoxue Xuebao vol 45 no 1 pp 26ndash302010

[85] K Irie T Sato I Tanaka J-I Nakajima M Kawaguchi and THimi ldquoCardiotonic effect of Apocynum venetum L extracts onisolated guinea pig atriumrdquo Journal of Natural Medicines vol63 no 2 pp 111ndash116 2009

[86] J Zhang X Xie C Li and P Fu ldquoSystematic review of the renalprotective effect of Astragalusmembranaceus (root) on diabeticnephropathy in animal modelsrdquo Journal of Ethnopharmacologyvol 126 no 2 pp 189ndash196 2009

[87] J Y Zhou Y Fan J L Kong D Z Wu and Z B Hu ldquoEffects ofcomponents isolated fromAstragalus membranaceus Bunge oncardiac function injured by myocardial ischemia reperfusion inratsrdquoChina Journal of ChineseMateriaMedica vol 25 no 5 pp300ndash302 2000


[88] H-W Zhu Z-F Shi and Y-Y Chen ldquoEffect of extract of ginkgobilboa leaf on early diabetic nephropathyrdquo Chinese Journal ofIntegrated Traditional and Western Medicine vol 25 no 10 pp889ndash891 2005

[89] J Lu and H He ldquoClinical observation of Gingko bilobaextract injection in treating early diabetic nephropathyrdquoChineseJournal of Integrative Medicine vol 11 no 3 pp 226ndash228 2005

[90] X-S Li W-Y Zheng S-X Lou X-W Lu and S-H YeldquoEffect of ginkgo leaf extract on vascular endothelial function inpatients with early stage diabetic nephropathyrdquo Chinese Journalof Integrative Medicine vol 15 no 1 pp 26ndash29 2009

[91] X-S Li X-J Fu and X-J Lang ldquoEffect of extract of Gingkobiloba on soluble intercellular adhesion molecule-1 and solublevascular cell adhesionmolecule-1 in patients with early diabeticnephropathyrdquo Chinese Journal of Integrated Traditional andWestern Medicine vol 27 no 5 pp 412ndash414 2007

[92] WZhouHChai PH LinA B LumsdenQYao andCChenldquoClinical use and molecular mechanisms of action of extract ofGinkgo biloba leaves in cardiovascular diseasesrdquoCardiovascularDrug Reviews vol 22 no 4 pp 309ndash319 2004

[93] S-H Lee Y-S Kim S-J Lee and B-C Lee ldquoThe pro-tective effect of Salvia miltiorrhiza in an animal model ofearly experimentally induced diabetic nephropathyrdquo Journal ofEthnopharmacology vol 137 no 3 pp 1409ndash1414 2011

[94] D de Zeeuw R Agarwal M Amdahl et al ldquoSelective vita-min D receptor activation with paricalcitol for reduction ofalbuminuria in patients with type 2 diabetes (VITAL study) arandomised controlled trialrdquoThe Lancet vol 376 no 9752 pp1543ndash1551 2010

[95] W Buchwald P L Mikolajczak A Krajewska-Patan et alldquoInvolvement of the different extracts from roots of Salviamiltiorrhiza bunge on acute hypobaric hypoxia-induced cardio-vascular effects in ratsmdashpreliminary reportrdquo Polish Journal ofVeterinary Science vol 15 pp 693ndash701 2012

[96] C M Li X L Dong X D Fan et al ldquoAqueous extract ofdanshen (Salvia miltiorrhiza Bunge) protects ovariectomizedrats fed with high-fat diet from endothelial dysfunctionrdquoMenopause vol 20 pp 100ndash109 2013

[97] J-S Zhu G M Halpern and K Jones ldquoThe scientific rediscov-ery of an ancient Chinese herbal medicine cordyceps sinensispart Irdquo Journal of Alternative and ComplementaryMedicine vol4 no 3 pp 289ndash303 1998

[98] L-Q Song Y Si-Ming M Xiao-Peng and J Li-Xia ldquoTheprotective effects of Cordyceps sinensis extract on extracellularmatrix accumulation of glomerular sclerosis in ratsrdquo AfricanJournal of Pharmacy and Pharmacology vol 4 no 7 pp 471ndash478 2010

[99] X F Yan Z M Zhang H Y Yao et al ldquoCardiovascular protec-tion and antioxidant activity of the extracts from the myceliaof cordyceps sinensis act partially via adenosine receptorsrdquoPhytotherapy Research vol 27 no 11 pp 1597ndash1604 2013

[100] W Xue J Lei X Li and R Zhang ldquoTrigonella foenumgraecum seed extract protects kidney function andmorphologyin diabetic rats via its antioxidant activityrdquo Nutrition Researchvol 31 no 7 pp 555ndash562 2011

[101] M G Friedrich CM Kramer D K Sodickson S D Flamm PBuser and S Neubauer ldquoMeeting highlights of the 10th annualscientific sessions of the Society for Cardiovascular MagneticResonance and 6th annual meeting of the Working Group forCardiovascular Magnetic Resonance of the European Societyof Cardiology Rome Italy February 2ndash4 2007rdquo Journal of the

American College of Cardiology vol 50 no 10 pp 983ndash9872007

[102] U N Tripathi and D Chandra ldquoThe plant extracts ofMomordica charantia and Trigonella foenum graecum haveantioxidant and anti-hyperglycemic properties for cardiac tis-sue during diabetes mellitusrdquo Oxidative Medicine and CellularLongevity vol 2 no 5 pp 290ndash296 2009

[103] B Raghavan and S K Kumari ldquoEffect of Terminalia arjuna stembark on antioxidant status in liver and kidney of alloxan diabeticratsrdquo Indian Journal of Physiology and Pharmacology vol 50 no2 pp 133ndash142 2006

[104] A Parveen R Babbar S Agarwal A Kotwani and M FahimldquoMechanistic clues in the cardioprotective effect of terminaliaarjuna bark extract in isoproterenol-induced chronic heartfailure in ratsrdquo Cardiovascular Toxicology vol 11 no 1 pp 48ndash57 2011

[105] Y Li T H-W Huang and J Yamahara ldquoSalacia root a uniqueAyurvedic medicine meets multiple targets in diabetes andobesityrdquo Life Sciences vol 82 no 21-22 pp 1045ndash1049 2008

[106] Y Li L He Y Qi et al ldquoThe Ayurvedic medicine Salaciaoblonga attenuates diabetic renal fibrosis in rats suppression ofangiotensin IIAT1 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2011 Article ID 807451 12 pages2011

[107] Y Li G Peng Q Li et al ldquoSalacia oblonga improves car-diac fibrosis and inhibits postprandial hyperglycemia in obesezucker ratsrdquo Life Sciences vol 75 no 14 pp 1735ndash1746 2004

[108] S SGhoshHDMassey R Krieg et al ldquoCurcumin amelioratesrenal failure in 56 nephrectomized rats role of inflammationrdquoAmerican Journal of Physiology Renal Physiology vol 296 no5 pp F1146ndashF1157 2009

[109] W Yu J Wu F Cai et al ldquoCurcumin alleviates diabeticcardiomyopathy in experimental diabetic ratsrdquo PLoS ONE vol7 Article ID e52013 2012

[110] K S Jayachandran M Khan K Selvendiran S N Devarajand P Kuppusamy ldquoCrataegus oxycantha extract attenuatesapoptotic incidence in myocardial ischemia-reperfusion injuryby regulating akt and Hif-1 signaling pathwaysrdquo Journal ofCardiovascular Pharmacology vol 56 no 5 pp 526ndash531 2010

[111] M A Lacaille-Dubois U Franck and H Wagner ldquoSearchfor potential angiotensin converting enzyme (ACE)-inhibitorsfrom plantsrdquo Phytomedicine vol 8 no 1 pp 47ndash52 2001

[112] X Li X Cui X Sun X Li Q Zhu and W Li ldquoMangiferinprevents diabetic nephropathy progression in streptozotocin-induced diabetic ratsrdquo Phytotherapy Research vol 24 no 6 pp893ndash899 2010

[113] S Muruganandan S Gupta M Kataria J Lal and P KGupta ldquoMangiferin protects the streptozotocin-induced oxida-tive damage to cardiac and renal tissues in ratsrdquo Toxicology vol176 no 3 pp 165ndash173 2002

[114] F Turgut O Bayrak F Catal et al ldquoAntioxidant and protectiveeffects of silymarin on ischemia and reperfusion injury in thekidney tissues of ratsrdquo International Urology and Nephrologyvol 40 no 2 pp 453ndash460 2008

[115] P R Rao andR K Viswanath ldquoCardioprotective activity of sily-marin in ischemia-reperfusion-induced myocardial infarctionin albino ratsrdquo Experimental and Clinical Cardiology vol 12 no4 pp 179ndash187 2007

[116] S Sen S Chen B Feng Y Wu E Lui and S ChakrabartildquoPreventive effects of NorthAmerican ginseng (Panax quinque-folium) on diabetic nephropathyrdquo Phytomedicine vol 19 no 6pp 494ndash505 2012


[117] H-J Yin Y Zhang and Y-R Jiang ldquoEffect of folium panaxquinquefolium saponins on apoptosis of cardiac muscle cellsand apoptosis-related gene expression in rats with acutemyocardial infarctionrdquoChinese Journal of Integrated Traditionaland Western Medicine vol 25 no 3 pp 232ndash235 2005

[118] Z Q Liu Q Z Li and G J Qin ldquoEffect of Astragalus injectionon platelet function and plasma endothelin in patients withearly stage diabetic nephropathyrdquo Chinese Journal of IntegratedTraditional and Western Medicine vol 21 no 4 pp 274ndash2762001

[119] M Li W Wang J Xue Y Gu and S Lin ldquoMeta-analysisof the clinical value of Astragalus membranaceus in diabeticnephropathyrdquo Journal of Ethnopharmacology vol 133 no 2 pp412ndash419 2011

[120] L Zhou Z Zuo andM S S Chow ldquoDanshen an overview of itschemistry pharmacology pharmacokinetics and clinical userdquoJournal of Clinical Pharmacology vol 45 no 12 pp 1345ndash13592005

[121] V Tripathi B Singh R Tripathi et al ldquoTerminalia arjuna itspresent statusrdquo Oriental Journal of Chemistry vol I pp 1ndash161996

[122] A Shehzad T Ha F Subhan and Y S Lee ldquoNew mechanismsand the anti-inflammatory role of curcumin in obesity andobesity-related metabolic diseasesrdquo European Journal of Nutri-tion vol 50 no 3 pp 151ndash161 2011

[123] S K Verma V Jain andR Khamesra ldquoCrataegus oxyacanthamdasha cardioprotective herbrdquo Journal ofHerbalMedicine andToxicol-ogy vol 1 pp 65ndash71 2007

[124] S Prabhu M Jainu K E Sabitha and C S Shyamala DevildquoEffect of mangiferin on mitochondrial energy production inexperimentally induced myocardial infarcted ratsrdquo VascularPharmacology vol 44 no 6 pp 519ndash525 2006

[125] S C Pradhan and C Girish ldquoHepatoprotective herbaldrug silymarin from experimental pharmacology to clinicalmedicinerdquo Indian Journal of Medical Research vol 124 pp491ndash504 2006

[126] A S Attele J A Wu and C-S Yuan ldquoGinseng pharmacologymultiple constituents and multiple actionsrdquo Biochemical Phar-macology vol 58 no 11 pp 1685ndash1693 1999

[127] A H MacLennan S P Myers and A W Taylor ldquoThe con-tinuing use of complementary and alternative medicine inSouth Australia costs and beliefs in 2004rdquo Medical Journal ofAustralia vol 184 no 1 pp 27ndash31 2006

[128] J-P Cosyns ldquoAristolochic acid and ldquoChinese herbs nephropa-thyrdquo a review of the evidence to daterdquo Drug Safety vol 26 no1 pp 33ndash48 2003

[129] W Chau R Ross J Y Z Li T Y Yong S Klebe and JA Barbara ldquoNephropathy associated with use of a Chineseherbal product containing aristolochic acidrdquoMedical Journal ofAustralia vol 194 no 7 pp 367ndash368 2011

[130] F D Debelle J-L Vanherweghem and J L Nortier ldquoAris-tolochic acid nephropathy a worldwide problemrdquo KidneyInternational vol 74 no 2 pp 158ndash169 2008

[131] K Wojcikowski D W Johnson and G Gobe ldquoMedicinalherbal extractsmdashrenal friend or foe part one the toxicities ofmedicinal herbsrdquo Nephrology vol 9 no 5 pp 313ndash318 2004

[132] N M Davies and J A Yanez ldquoToxicology and safety offlavonoidsrdquo in Flavonoid Pharmacokinetics Methods of AnalysisPreclinical and Clinical Pharmacokinetics Safety and Toxicol-ogy pp 249ndash280 John Wiley amp Sons 2013

[133] J F E Mann H C Gerstein J Poque J Bosch and S YusufldquoRenal insufficiency as a predictor of cardiovascular outcomesand the impact of ramipril theHOPE randomized trialrdquoAnnalsof Internal Medicine vol 134 no 8 pp 629ndash636 2001

[134] GManjunath H Tighiouart H Ibrahim et al ldquoLevel of kidneyfunction as a risk factor for atherosclerotic cardiovascularoutcomes in the communityrdquo Journal of the American Collegeof Cardiology vol 41 no 1 pp 47ndash55 2003

[135] M G Shlipak R Katz B Kestenbaum et al ldquoRapid declineof kidney function increases cardiovascular risk in the elderlyrdquoJournal of the American Society of Nephrology vol 20 no 12 pp2625ndash2630 2009

[136] W B A Eijkelkamp P A de Graeff D J van Veldhuisen etal ldquoEffect of first myocardial ischemic event on renal functionrdquoAmerican Journal of Cardiology vol 100 no 1 pp 7ndash12 2007

[137] H L Hillege W H van Gilst D J Van Veldhuisen et alldquoAccelerated decline and prognostic impact of renal functionafter myocardial infarction and the benefits of ACE inhibitionthe CATS randomized trialrdquo European Heart Journal vol 24no 5 pp 412ndash420 2003

[138] N H Mashour G I Lin and W H Frishman ldquoHerbalmedicine for the treatment of cardiovascular disease clinicalconsiderationsrdquo Archives of Internal Medicine vol 158 no 20pp 2225ndash2234 1998

[139] V Jha ldquoHerbal medicines and chronic kidney diseaserdquoNephrol-ogy vol 15 no 2 pp 10ndash17 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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patients still develop intractable disease [16] Moreover withthe development of resistance to many conventional thera-pies such as diuretics and inotropes there is an increasingmovement toward novel therapies [17] This has promptedmuch interest in the use of traditional medicines for thetreatment of CRS Thus the current review provides adetailed discussion summarizing the current understandingof herbal and traditional medicines for the management andpotential treatment and reversal of CRS-related pathogenesis

2 Cardiorenal Metabolic SyndromeCurrent Understanding and Classification

The CRS has been recently defined as a disorder of the heartand kidneys whereby acute or chronic dysfunction in oneorgan may induce acute or chronic dysfunction in the other[18] Several groups have proposed that each dysfunctionalorgan has the ab initio ability to initiate and perpetuatedisease in the other organ through hemodynamic neu-rohormonal and immunologicbiochemical feedback path-ways [11] Moreover the current disease definition has beenexpanded into 5 subtypes that reflect the pathophysiologytime-frame and bidirectional nature of heart and kidneyinteractions [19] Categorizing CRS based on the responseto various treatment modalities is practical and ideal in thedesign of a treatment including the possibilities of newprevention and management algorithms [20] Type 1 CRSreflects rapid worsening of cardiac function leading to acutekidney injury Type 2 CRS comprises chronic abnormalitiesin cardiac function leading to progressive chronic kidneydisease Type 3 CRS consists of an abrupt worsening ofrenal function causing acute cardiac dysfunction Type 4 CRSdescribes primary chronic kidney disease causing decreasedcardiac function ventricular hypertrophy diastolic dysfunc-tion andor an increased risk of adverse cardiovascularevents Type 5 CRS reflects the presence of combined cardiacand renal dysfunction due to acute or chronic systemicdisorders [20 21]

3 Cardiorenal MetabolicSyndrome Pathophysiology

The pathophysiology of cardiorenal syndrome involves inter-related hemodynamic and neurohormonal mechanismsincluding sympathetic overactivity the renin-angiotensin-aldosterone system various chemical mediators (nitric oxideprostaglandins endothelins etc) and oxidative stress [1722] Traditionally CRS is characterized by an impairment ofkidney function caused by hypoperfusion and cardiac pumpfunction failure [23 24] The bidirectional interplay betweenthe heart and the kidneys and the impact of numerousother factors on this interaction have been shown to befundamental in the pathogenesis of CRS [20] (Figure 1)However the detailed mechanisms underlying the interplayof CRS still have not been completely delineated [5]

31 DirectHemodynamicMechanisms Theheart and kidneyshave been known to share responsibility for maintaining

hemodynamic stability through a tight-knit relationship thatcontrols cardiac output volume status and vascular tone [25]CRS is initiated by left ventricular systolic dysfunction whichleads to decreased renal blow flow followed by activation offluid retention mechanisms This subsequently causes wors-ening of cardiac pumping capacity resulting in initiating avicious cycle and eventual organ deterioration [11] Howeverthe simple hemodynamic variations are only a part of thecomplex pathophysiology of CRS [1 20] The pathophysiol-ogy of kidney dysfunction in the context of heart diseaseis much more complex than a simple reduction of cardiacoutput [5] Several other mechanisms are involved and couldpotentially be considered as a basis for the therapeutic man-agement of this syndrome [20] The pathophysiology of thecardiorenal syndrome involves interrelated hemodynamicand neurohormonal mechanisms including the sympatheticnervous system (SNS) the renin-angiotensin-aldosteronesystem (RAAS) and endothelin and arginine vasopressinsystem activation [22] Moreover neurohormones are strongprecipitants and are also mediators of an oxidative injurycascade that can lead to widespread endothelial dysfunctioninflammation and cell death in the CRS [11]

32 Autonomic Nervous System The adverse consequencesof sympathetic hyperactivity are one of the harmful compen-satory mechanisms that occur in CRS [11] Sustained elevatedadrenergic tone causes a reduction in 120573-adrenergic receptordensity particularly 120573

1 within the ventricular myocardium

as well as uncoupling of the receptor from the intracellularsignallingmechanisms [26] Less well appreciated are the sys-temic effects of renal sympathetic stimulation [11] Howeverincreased kidney sympathetic activation and catecholaminerelease in the setting of reduced catecholamine clearance withan already impaired kidney function are a part of the self-deteriorating cycle that aggravates kidney dysfunction andheart failure [27]

33 The Renin-Angiotensin-Aldosterone System The CRSoccurs with both hypoperfusion associated with decreasedcardiac output and venous congestion [25] Downregulationof renal perfusion stimulates renin secretion which in turnactivates the RAAS followed by activation of the SNS [28]The extreme sodium avidity and ventricular remodelingconferred by RAAS elaboration in heart failure are a mal-adaptive response to altered haemodynamics sympatheticsignalling and progressive renal dysfunction [11] One of thedeleterious actions of the RAAS in the CRS is the activationof nicotinamide adenine dinucleotide phosphate (NADPH)oxidase by angiotensin II (Ang II) resulting in formation ofreactive oxygen species (ROS) [29] Ang II potentially actingthrough changes in the cellular redox status is implicated invascular inflammation via the nuclear factor kappaB (NF-120581B)pathway which induces production of adhesion molecules[30 31] Angiotensin-converting enzyme (ACE) inhibitionand aldosterone antagonism have shown a beneficial effect incardiac failure by inhibiting the intracardiac RAAS reductionin adrenergic tone improvement in endothelial functionand prevention of myocardial fibrosis [32] Moreover ACE







Kidney failure



Heart failureAnemia


uarr Adenosine






































[86 87]


[88ndash92]



[93ndash96]





[100ndash102]



[103 104]




[108 109]



[110 111]





[114 115]










1and 120573





1






7 Conclusion






References






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Kidney failure



Heart failureAnemia


uarr Adenosine






































[86 87]


[88ndash92]



[93ndash96]





[100ndash102]



[103 104]




[108 109]



[110 111]





[114 115]










1and 120573





1






7 Conclusion






References






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































[86 87]


[88ndash92]



[93ndash96]





[100ndash102]



[103 104]




[108 109]



[110 111]





[114 115]










1and 120573





1






7 Conclusion






References






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















1and 120573





1






7 Conclusion






References






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article management of cardiorenal metabolic...

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