· web viewprovide negative feedback control in response to increased avp-induced osmotic water...

Kidney Tubules intertubular vasculature and glomeruli cross-talk

David A Ferenbach12 and Joseph V Bonventre134

1Renal Division and Biomedical Engineering Division Brigham and Womenrsquos

Hospital Department of Medicine Harvard Medical School Boston

Massachusetts USA

2Centre for Inflammation Research Queenrsquos Medical Research Institute

University of Edinburgh Edinburgh UK

3Harvard-Massachusetts Institute of Technology Division of Health Sciences

and Technology Cambridge Massachusetts USA

4Harvard Stem Cell Institute Cambridge Massachusetts USA

1

Abstract

The kidney mediates the excretion or conservation of water and electrolytes in

the face of changing fluid and salt intake and losses To ultrafilter and

reabsorb the exact quantities of free water and salts to maintain euvolemia a

range of endocrine paracrine and hormonal signaling systems have evolved

linking the tubules capillaries glomeruli arterioles and other intrinsic cells of

the kidney This review addresses the paracrine signals recognized to

mediate communication between adjacent and distant tubular cells of each

nephron and mechanisms by which tubules feedback and influence

glomerular function Our current understanding of pathway functions in health

and disease is reviewed as are future therapeutic options to protect the

healthy and injured kidney

Key words kidney tubule epithelial cell tubuloglomerular feedback hypertension fibrosis

Key points1 Multiple molecules are recognized to facilitate tubule to tubule

signalling within the kidney

2 Paracrine agents also have actions as vasoconstrictors or vasodilators

of the renal vasculature

3 ATP ATII bradykinin carbon monoxide superoxide and prostaglandin

derivatives mediate feedback at the macula densa from tubule to

glomerulus

4 Recent work has demonstrated pathogenic roles for signaling from

senescent or growth arrested tubular cells in aging and renal disease

2

IntroductionThe kidneys mediate waste excretion water and electrolyte balance They

also maintain systemic blood pressure bone calcification and stimulate red

blood cell production In addition to responding to systemic hormonal cues

autocrine and paracrine signaling pathways exist within the kidney itself(1)

These signaling pathways may be adaptive during normal physiological

function or maladaptive in disease They facilitate communication among

podocytes vascular endothelium stroma and epithelial cells at different levels

of the nephron to respond to physiologic and pathophysiological changes (2)

This article reviews our current understanding of signaling mechanisms

among tubular interstitial vascular and glomerular cells with an emphasis on

recent progress in this field The relevance of these systems in health

disease and therapy will be discussed

Adenosine Triphosphate (ATP)

ATP is the essential energy source fueling the metabolic reactions within all

cells(3) While generated within mitochondria and predominantly intracellular

it is now recognized as a paracrine signal that acts among renal tubules(4 5)

The stimuli and mechanisms responsible for tubular extracellular ATP (eATP)

secretion remain incompletely understood Evidence in vitro suggests exit

from the cell via membrane channels(6) and release via vesicular fusion with

the membrane (7)

At one-thousandth of the intracellular concentration eATP facilitates autocrine

and paracrine signaling between renal tubular cells It ligates two families of

purinergic receptors ndash ionotropic (P2X) and metabolotropic (P2Y) (8) The

3

functions and potential therapeutic relevance of these receptors are the focus

of ongoing research There is evidence for the expression at the mRNA level

and activation of all P2XR and some P2YRs within the kidney (9)

Tubular cells release eATP in response to cell swelling or increased renal

tubular flow This allows flow rates in one nephron segment to influence NaCl

adsorption extracellular fluid volume status electrolyte balance and blood

pressure by paracrine mechanisms (1) eATP also impacts renal

hemodynamics causing renal vasodilation via P2XR and P2YR activation(10)

Pathological functions of eATP

Activation of the P2X7 receptor results in microvascular dysfunction and

regional hypoxia when angiotensin II is infused into rats and these effects

may contribute to progression of renal injury induced by chronic angiotensin

II(11)

In the mouse P2X7 receptor inhibition protects against IRI with protection

also seen in the UUO model in rats(11 12) Recent studies show that

collecting duct (CD) principal cells express P2Y12R Blockade potentiated the

effects of ddAVP in vitro and increased urinary concentrating ability in animals

with lithium-induced nephrogenic diabetes insipidus(13) Human trials of

P2X7R blockade have been motivated by the hypothesis that inhibitors would

decrease inflammation have failed to demonstrate clinical efficacy in diseases

such as rheumatoid arthritis (14)

4

In the extracellular environment ATP and ADP are converted to adenosine

with ecto-5rsquo-nucleotidase CD73 a major enzyme responsible Rats lacking

CD73 or adenosine A2BR (upregulated in diabetic nephropathy) develop

worsened diabetic nephropathy(15)

Few studies explore associations between gene polymorphisms of ATP

receptors and human disease One study reported P2X7R polymorphism

influencing BP(16) but has not been replicated(17)

Endothelin-1

Endothelin-1 (ET-1) is a vasoconstrictor which regulates salt and water

clearance and influences systemic BP ET-1 is expressed within the tubular

cells of the inner medullary CD and secreted across the basolateral

membrane ET-1 production and secretion is stimulated by volume loading

augmented by inflammatory cytokines in vivo and is elevated in most cases

of clinical CKD(18) ET-1 synthesis in the canine kidney is inhibited by both

prostacyclins and nitric oxide (NO)(19)

There are two groups of recognized ET receptors within the kidney ETA and

ETB (20) Both are expressed in the inner medullary CD allowing autocrine

and paracrine signaling to take place in these cells ET-1 and its receptors

provide negative feedback control in response to increased AVP-induced

osmotic water permeability Thick ascending limb (TAL) and CD tubules both

express ETB receptors and stimulation by ET-1 causes inhibition of NaCl

transport and stimulation of neuronal NOS The increased production of NO

5

then inhibits Na+K+-ATPase and ENaC within the distal convoluted tubules

(DCT) and the CDs(21)

Pathological role for ET-1 in renal disease

Increased ET-1 levels are believed to be pathogenic in diabetic and non

diabetic CKD contributing to renal hypoxia inflammation and fibrosis(18 21)

These effects are predominantly due to ligation of the renal ETA receptor

promoting vasoconstriction cell proliferation and matrix accumulation(18)

Clinical trials of endothelin receptor antagonists demonstrate an anti-

proteinuric effects beyond those expected from their anti-hypertensive actions

(reviewed in (18 22)) Analyses have shown that lowered eGFR and

diabetes predispose patients to fluid retention complicating the use of

endothelin receptor antagonists in renal patients(23)

Nitric Oxide

The signaling molecule NO is produced by nitric oxide synthase (NOS)

enzymes in many tissue types altering tissue tone and blood pressure All

three NOS enzymes are present within the tubular cells of the kidney(24)

NOS3 is expressed in cells of the proximal convoluted tubule (PCT) TAL and

CD NOS2 within PCT TAL DCT and CD cells while NOS1 is found at low

levels in the TAL and CD

Tubular epithelial NO exerts autocrine and paracrine effects promoting

natriuresis and diuresis and conveys signals to the adjacent vasculature(25)

Physiologic renal NO release has beneficial effects on renal hemodynamics

6

and function while experimental models with reduced NO demonstrate

increased effects of angiotensin (ATII)(26)

Role of Nitric Oxide in renal pathology

Renal NO levels decline with advancing stages of CKD(27) Insulin simulates

NOS3 within the kidney and insulin deficiency may influence both blood

pressure and renal perfusion via effects on NO(28) Aristolochic acid

nephropathy (AAN) induces tubular injury and transient reductions in renal NO

generation Murine AAN studies show that arginine supplementation

increases NO availability reduces free radical generation and reduces renal

injury(29) Studies of experimental IRI demonstrate that pre-induction of NO

ameliorates disease severity while co-treatment with NO-inhibitors abolishes

protection(30) Potentiating tubular NO production merits investigation as a

translational protective therapy for acute and chronic renal injury(31)

Dopamine

Renal dopamine is generated within the cells of the PCT and secreted

through the apical and basolateral membranes exhibiting local paracrine

effects and hormonal actions via the blood stream on distal nephron

segments (32)

7

Dopamine signals via five known receptors broadly grouped into D1-like (D1

and D5 receptors) and D2-like (D2 D3 and D4) groups In the kidney the D1

receptor family is expressed throughout the nephron juxtaglomerular

apparatus and vasculature(33) D1-like receptors inhibit salt and water

transport in tubular cells relax vascular smooth muscle and inhibit

sympathetic nervous system activity(34 35) Stimulation of D1-like receptors

is associated with natriuresis and diuresis in states of sodium loading without

a requirement for increased renal blood flow(36 37) During sodium depletion

the effects of D1-like receptor ligation are largely lost with recent work

implicating an interaction with the renin-angiotensin signaling pathway(38)

Renal D2 receptors also impact salt and water uptake and vascular tone

Studies examining polymorphisms within the human D2 receptor gene have

shown correlation with hypertension in clinical cohorts(35) Mice lacking D2

receptors exhibit worsened renal injury and fibrosis independent of BP with

miRNA 214 implicated as pathogenic(39 40) D3 receptors are the

predominant renal D2-like receptor and are expressed in proximal tubules

TALs and the cortical CD in addition to podocytes and blood vessels(41)

D3R in synergy with AT2R enhances natriuresis and diuresis via the

ERK12-MAPK pathway(42)

D4 receptors are expressed in the CDs proximal tubules and TAL When

stimulated D4 receptors oppose water and sodium uptake via downregulation

of AT2 type I receptors(43) Compensatory mechanisms exist as D4 receptor

8

knockout mice retain the ability to excrete an acute sodium load in vivo but

display higher blood pressures than WT littermates(44)

Role of dopamine and dopamine receptors in hypertension

Selective dopamine deficiency in the murine kidney is associated with

progressive fibrosis(45) and in man dopamine deficiency is linked with salt-

sensitive hypertension(46) Current knowledge of essential hypertension

implicates a desensitization of the kidney to endogenous dopamine

production via changes in expression of the dopamine signaling via the G

Protein-Coupled Receptor Kinase 4 (GRK4) (47) Clinical cohort studies have

identified GRK4 polymorphisms as contributing to hypertension and treatment

responses (48 49) Mice with D2-receptor family defects have renin-

dependent hypertension ameliorated by upregulation of D5 receptors (50) In

wild type mice treatment with a D3-receptor antagonist induces hypertension

when combined with chronically elevated sodium intake(51) Dopamine

produced by the tubules dopamine acts throughout the nephron to enhance

sodium excretion via its receptors Defects of production or receptor function

leads to abnormal sodium handling and salt-sensitive hypertension(46)

Angiotension II

ATII is also synthesized and released from the proximal tubule and impacts

renal water and electrolyte uptake ATII stimulates sodium uptake by the

cells of the PCT TAL and the CD(52) In health ATII augments salt and water

uptake via the tubular AT1 receptor with the renal AT1R a driver of systemic

hypertension(53) Via hormonal or paracrine signaling ATII also induces

9

proliferation hypertrophy inflammation and matrix production by tubular cells

(54)- all features common to progressive renal disease Additionally ATII

mediates tubule-tubule crosstalk indirectly via interstitial pericytes and

fibrocytes (55)

Angiotensin II in renal disease

ATII is the main effector of the renin-angiotensin system in the kidney

promoting fibrosis and tubular cell loss Excess ATII production is a common

feature of CKD including that resulting from diabetic nephropathy(54) ATII

uptake within the tubular cells themselves stimulates production of TGF-β1

interstitial inflammation pericyte detachment of the endothelium activation

and transdifferentiation to myofibroblasts vascular rarefaction

vasoconstriction secondary ischemia and tubular cell loss(56) Treatment

with ACE inhibitors or ATII receptor blockers both improve outcome in clinical

diabetic nephropathy and in experimental models decrease TGF-β1

signaling lower proteinuria and promote epithelial cell survival(57-59)

Bradykinin

Bradykinin is a vasodilatory nine-amino acid peptide with effects on the heart

kidney and systemic blood vessels(60) Within the kidney bradykinin is

synthesized by the TAL and CD and secreted across apical and basolateral

membranes(61) Many of bradykininrsquos effects occur at a local tissue level

influencing blood pressure via release of NO and prostaglandins(60)

Through interaction with bradykinin B1 and B2 receptors bradykinin promotes

diuresis and natriuresis Bradykinin B1 receptors are expressed by

10

differentiating renal tubules(62) and mediate potentially pro-inflammatory

effects with B2 receptor knockout mice demonstrating salt sensitive

hypertension and renal dysgenesis Mice lacking B1 receptors are

normotensive and protected from inflammation and AKI(63)

Bradykinin in renal disease

Bradykinin antagonizes activation of the renin-angiotensin system opposing

vasoconstriction hypoxia and pro-inflammatory activation(61 64) Bradykinin

synthesis is protective against hypertensive renal damage and diabetic

nephropathy(65 66) Studies of the selective kininases ebelactone B and

poststatin indicate promise as novel antihypertensive agents(67)

Bradykininrsquos actions are prolonged by the use of ACE inhibitors with

potentiation of renal bradykinin a potential advantageous therapeutic effect of

the ACE inhibitors in addition to a cause of angioedema(68) Both kinin

receptor inhibition and kinin B1 and B2 receptor knockout mice are protected

against cisplatin-induced AKI(69 70) with B1 receptor antagonists also

reducing fibrosis after experimental UUO presumably due to inhibition of

bradykininrsquos pro-inflammatory actions including promotion of migration of

immune cells to injured tissue (71)

Prostaglandins

Three pathways of arachidonic acid metabolism exist mediated by

cyclooxygenase (COX) lipoxygenase and cytochrome P450 enzymes Of

these we will focus on the cyclooxygenase generated compounds which are

believe to be the most important for renal tubule-tubule signaling (2) although

11

other arachidonic acid metabolites (eg epoxyeicosatrienoic acids or 20-

hydroxyeicosatetraenoic acid derived from the P450 system) can alter

epithelial sodium transport glomerular hemodynamics and vascular reactivity

and have anti-inflammatory effects(72 73)

Inducible COX2 generates prostaglandin I2 (PGI2) and is expressed

within the cortical thick ascending loop of Henle (TALH) while the cells of the

medullary TALH and CD express constitutive COX1(74) Both COX1 and

COX2 enzymes produce PG compounds in the normal and diseased kidney

The metabolites of COX1 and COX2 have important roles within the kidney

regulating blood flow affecting the release of renin and mediating NaCl

excretion (74) While these functions fulfill important physiologic roles

increased levels of COX metabolites are seen in disease states and likely

contribute to inflammatory injury

Prostaglandins in renal disease

COX2 derived prostanoids are renal vasodilators(75) and the inhibition of this

effect by non-steroidal anti inflammatory drugs likely contributes to their

nephrotoxicity(76) Levels of COX2 increase in response to renal insults

aging diabetes(77) heart failure(78) and lithium treatment(79) with COX2

inhibition reported to be protective(80) Within the kidneys of diabetics

COX2rsquos vasodilatory effects may be maladaptive with human studies

demonstrating COX2 inhibition reversing hyperfiltration(81) In isolated

glomeruli fluid flow sheer stress resulted in increased albumin permeability

which was reversed by indomethacin a COX inhibitor(82)

12

Cytokine production by senescent or G2M arrested tubular cells

Our group has demonstrated that models of severe and progressive renal

injury (UUO AAN and severe IRI) show accumulation of tubular cells in the

G2M phase of the cell cycle (83) These cells adopt a pro-fibrotic profile in

vivo and in vitro secreting growth factors including connective tissue growth

factor (CTGF) and TGF-β1 in addition to increased collagen 4α1 and 1α1

mRNA(83) Thus cell cycle arrest can induce paracrine signaling from tubular

cells themselves which can be a key component of the fibrotic response to

renal injury a hypothesis supported by recent reports from other

laboratories(84-86) Pharmacological inhibition of G2M arrested cells

reduced fibrosis whereas increases in the G2M arrested proportion of cells in

the cell cycle exacerbated fibrosis(84-86)

Paracrine signaling is a recognized feature of senescent tubular cells

expressing p16INK4a(87) These cells accumulate with aging and renal

injury producing TGF-β1113097 EGF IGF-1 and VEGF promoting fibrogenesis

and further senescence with impaired tubular proliferation Studies in

progeroid mice demonstrate that depletion of senescent cells delays aging

and increases healthy lifespan(88)

Transgenic mice expressing the simian diphtheria toxin receptor allow the

study of the effects of selective repeated tubular injury on kidney signaling

function and scarring Repeated tubular injury results in tubular vascular and

glomerular loss with increased fibrosis (89) The response of tubular cells to

acute injury including expression of TGF-β acting in a paracrine and

13

autocrine way has been implicated as important in determining fibrotic

outcomes and eventual glomerulosclerosis(90 91)

Tubulo-glomerular feedback

Communication between tubules and the glomerulus is vital to maintain

homeostasis We have previously referred to indirect tubular-glomerular

feedback via peritubular capillary rarefaction and vasoconstriction(89) In

addition there are well-studied mechanisms of tubulo-glomerular feedback

(TGF) involving the macula densa (MD) The juxtaglomerular apparatus is

made up of renin-producing juxtaglomerular cells in the afferent arteriole and

the adjacent salt-sensing macula densa cells of the TALH of the distal

nephron derived from the same glomerulus (92) Altered NaCl concentration

in the tubular lumen of the distal nephron results in altered glomerular

arteriolar resistance (73) Reduced tubular NaCl delivery results in increases

in single nephron glomerular filtration rate and vice versa(73 93) There are

also reports of contacts between the TALH and the efferent arteriole and

between tubular cells adjacent to the macula densa and the afferent arteriole

signaling via ATP release (92)

Changes in the distal nephron luminal fluid tonicity result in altered glomerular

hemodynamics via intracellular Ca2+ signaling Classic studies demonstrate

that Ca2+ flux is essential for TGF responses to altered NaCl delivery (94 95)

Briefly TGF is initiated when NaCl enters the MD cells via the two isoforms of

the NKCC2 channel (96) Recent use of multi-photon microscopy in vivo is

facilitating new studies and insights into the cells and processes involved(97)

14

Current understanding of TGF demonstrates dual roles for adenosine roles for

adenosine with carbon monoxide NO and kinin compounds as net

vasodilators with AT2 superoxide 20-hydroxyeicosatetraeonic acid (20-

HETE) and thromboxane all contributing to vasoconstriction(73)

Tubulo-glomerular feedback in renal disease

While TGF seeks to balance NaCl excretion via alterations in glomerular

filtration rate in sub-total nephrectomy models of chronic nephron loss a

partial reversal of the system has been observed with increased tubular NaCl

at the macula densa causing increases in single nephron GFR(73 98)

mediated in part by overactivity of NOS(99) Inappropriate activation of the

TGF system in diabetes contributes to the development of hyperfiltration(100)

Sodium glucose cotransporter 2 (SLGT2) inhibition in these patients reduced

clinical hyperfiltration via effects on macula densa cells and inhibition of

pathogenic TGF(101) Recent work shows reduced total and cardiovascular

mortality in diabetics taking SLGT2 inhibitors(102) potentially linking

regulation of tubular signaling to patient survival

Conclusions

Several pathways facilitate communication among adjacent proximate and

distant renal tubular cells vasculature and glomerulus This complex

communication system is highly adaptive under normal physiological states

but with pathology can turn maladaptive Better understanding of these

interactions in disease and the effects agents such as ACEi ARBs and

15

NSAIDs and and other drugs on these complex paracrine and autocrine

signaling pathways should provide interventional strategies to counter

maladaptive signals and responses Given the substantial impact of

hypertension diabetes and CKD on global health understanding maladaptive

communication pathways and acquiring tools to intervene and protect tubular

cells remains a pressing clinical need

16

Figure Legends

Figure 1 ndash Sites of tubular nitric oxide generation and its autocrine and

paracrine effects NO is generated via endothelial inducible and neuronal

nitric oxide synthases 12 and 3 thoughout the tubule It then exerts autocrine

and paracrine effects on surrounding tubules blood vessels and glomeruli

Figure 2 ndash Distribution of dopamine producing cells and dopamine

receptors within the tubular cells of the nephron Dopamine is released

from cells of the proximal convoluted tubule and exert both paracrine effects

and hormonal actions via interactions with different subtypes of dopamine

receptors on different nephron segments and uptake by blood vessels

Figure 3 ndash Paracrine effects of the secretory phenotype seen in G2M

arrested tubular epithelial cells The proportion of tubular cells in the G2M

phase of the cell cycle increases in response to severe or sustained renal

injuries These cells produce factors including CTGF and TGF-β1 These

exert paracrine effects on both neighboring tubular cells as well as interstitial

and endothelial cells and macrophage numbers and phenotypes There is

deposition of collagen within the kidney

Figure 4 ndash Tubulo-glomerular feedback from the macula densa to the

glomerulus In response to altered distal flow and chloride delivery cells of

the macula densa initiate a signaling cascade involving generation of

molecules via COX2 nitric oxide synthase and ATP release (via metabolism

17

to adenosine) These exert effects on extraglomerular mesangial cells and on

the afferent arteriole- causing net constriction or dilatation and resultant

changes in GFR

18

Figure 1

19

20

21

Figure 2

22

Figure 3

23

Figure 4

24

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25

journal of physiology Cell physiology 2015 Mar 15308(6)C463-72 PubMed PMID 25588875 Pubmed Central PMCID 4360025This work demonstrates the therapeutic efficacy of targeting the P2X7 purinergic receptor in murine IRI13 Zhang Y Peti-Peterdi J Muller CE Carlson NG Baqi Y Strasburg DL et al P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus J Am Soc Nephrol 2015 Apr 8 PubMed PMID 25855780Rodent studies and in vitro work demonstrating that P2Y12 receptor blockade augments AVP action and increases urinary concrentrating ability- a finding with therapeutic relevance14 Stock TC Bloom BJ Wei N Ishaq S Park W Wang X et al Efficacy and safety of CE-224535 an antagonist of P2X7 receptor in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate J Rheumatol 2012 Apr39(4)720-7 PubMed PMID 2238234115 Tak E Ridyard D Kim JH Zimmerman M Werner T Wang XX et al CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy J Am Soc Nephrol 2014 Mar25(3)547-63 PubMed PMID 24262796 Pubmed Central PMCID 3935577Important studies in mice demonstrating the importance of adenosine and Adora2b receptors in attenuating experimental diabetic nephropathy16 Palomino-Doza J Rahman TJ Avery PJ Mayosi BM Farrall M Watkins H et al Ambulatory blood pressure is associated with polymorphic variation in P2X receptor genes Hypertension 2008 Nov52(5)980-5 PubMed PMID 1885239017 Ghiadoni L Rossi C Duranti E Santini E Bruno RM Salvati A et al P2X7 receptor polymorphisms do not influence endothelial function and vascular tone in neo-diagnosed treatment-naive essential hypertensive patients Journal of hypertension 2013 Dec31(12)2362-9 PubMed PMID 2422059018 Kohan DE Barton M Endothelin and endothelin antagonists in chronic kidney disease Kidney international 2014 Nov86(5)896-904 PubMed PMID 24805108 Pubmed Central PMCID 421661919 Chou SY Porush JG Renal actions of endothelin-1 and endothelin-3 interactions with the prostaglandin system and nitric oxide American journal of kidney diseases the official journal of the National Kidney Foundation 1995 Jul26(1)116-23 PubMed PMID 754193720 Boesen EI Endothelin receptors renal effects and blood pressure Current opinion in pharmacology 2015 Apr2125-34 PubMed PMID 25544397A recent review summarizing progress in our understanding of endothelin receptors and their antagonism in clinical renal disease21 Anguiano L Riera M Pascual J Soler MJ Endothelin Blockade in Diabetic Kidney Disease Journal of clinical medicine 20154(6)1171-92 PubMed PMID 26239552 Pubmed Central PMCID 448499322 Schneider MP Mann JF Endothelin antagonism for patients with chronic kidney disease still a hope for the future Nephrology dialysis transplantation official publication of the European Dialysis and Transplant

26

Association - European Renal Association 2014 Feb29 Suppl 1i69-i73 PubMed PMID 2449387223 Kohan DE Lambers Heerspink HJ Coll B Andress D Brennan JJ Kitzman DW et al Predictors of Atrasentan-Associated Fluid Retention and Change in Albuminuria in Patients with Diabetic Nephropathy Clin J Am Soc Nephrol 2015 Sep 410(9)1568-74 PubMed PMID 26153128 Pubmed Central PMCID 4559498The work explores the renal outcomes and complications of recent major clinical trials in endothelin receptor antagonism in diabetic patients with kidney disease24 Baylis C Nitric oxide synthase derangements and hypertension in kidney disease Curr Opin Nephrol Hypertens 2012 Jan21(1)1-6 PubMed PMID 22048724 Pubmed Central PMCID 327793425 Horita S Nakamura M Shirai A Yamazaki O Satoh N Suzuki M et al Regulatory roles of nitric oxide and angiotensin II on renal tubular transport World journal of nephrology 2014 Nov 63(4)295-301 PubMed PMID 25374825 Pubmed Central PMCID 422036426 Deng A Miracle CM Suarez JM Lortie M Satriano J Thomson SC et al Oxygen consumption in the kidney effects of nitric oxide synthase isoforms and angiotensin II Kidney Int 2005 Aug68(2)723-30 PubMed PMID 1601404927 Baylis C Nitric oxide deficiency in chronic kidney disease Am J Physiol Renal Physiol 2008 Jan294(1)F1-9 PubMed PMID 1792841028 Pandey G Makhija E George N Chakravarti B Godbole MM Ecelbarger CM et al Insulin regulates nitric oxide production in the kidney collecting duct cells J Biol Chem 2015 Feb 27290(9)5582-91 PubMed PMID 25533472 Pubmed Central PMCID 4342472Studies both in vitro and in experimental mice illustrating the role of insulin in regulating renal epithelial nitic oxide29 Decleves AE Jadot I Colombaro V Martin B Voisin V Habsch I et al Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury An old friend with new assets Experimental physiology 2015 Oct 7 PubMed PMID 2644279530 Koul V Kaur A Singh AP Investigation of the role of nitric oxidesoluble guanylyl cyclase pathway in ascorbic acid-mediated protection against acute kidney injury in rats Mol Cell Biochem 2015 Aug406(1-2)1-7 PubMed PMID 2614272831 Amaral JH Ferreira GC Pinheiro LC Montenegro MF Tanus-Santos JE Consistent antioxidant and antihypertensive effects of oral sodium nitrite in DOCA-salt hypertension Redox biology 2015 Jun 235340-6 PubMed PMID 26119848 Pubmed Central PMCID 449164632 Choi MR Kouyoumdzian NM Rukavina Mikusic NL Kravetz MC Roson MI Rodriguez Fermepin M et al Renal dopaminergic system Pathophysiological implications and clinical perspectives World journal of nephrology 2015 May 64(2)196-212 PubMed PMID 25949933 Pubmed Central PMCID 441912933 Carey RM The intrarenal renin-angiotensin and dopaminergic systems control of renal sodium excretion and blood pressure Hypertension 2013 Mar61(3)673-80 PubMed PMID 23407646 Pubmed Central PMCID 3577093

27

34 Zeng C Zhang M Asico LD Eisner GM Jose PA The dopaminergic system in hypertension Clinical science 2007 Jun112(12)583-97 PubMed PMID 1749294535 Armando I Konkalmatt P Felder RA Jose PA The renal dopaminergic system novel diagnostic and therapeutic approaches in hypertension and kidney disease Translational research the journal of laboratory and clinical medicine 2015 Apr165(4)505-11 PubMed PMID 25134060 Pubmed Central PMCID 430549936 Atkinson KF Kathem SH Jin X Muntean BS Abou-Alaiwi WA Nauli AM et al Dopaminergic signaling within the primary cilia in the renovascular system Frontiers in physiology 20156103 PubMed PMID 25932013 Pubmed Central PMCID 439920837 Zhang LN Li JX Hao L Sun YJ Xie YH Wu SM et al Crosstalk between dopamine receptors and the Na(+)K(+)-ATPase (review) Molecular medicine reports 2013 Nov8(5)1291-9 PubMed PMID 2406524738 Natarajan AR Eisner GM Armando I Browning S Pezzullo JC Rhee L et al The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans J Am Soc Nephrol 2015 May 14 PubMed PMID 25977313An important study in man illustrating interactions between the angiotensin and dopaminergic signaling systems in the normotensive population39 Zhang Y Jiang X Qin C Cuevas S Jose PA Armando I Dopamine D2 receptors effects on renal inflammation are mediated by regulation of PP2A function Am J Physiol Renal Physiol 2015 Aug 19ajprenal 00453 2014 PubMed PMID 2629037440 Han F Konkalmatt P Chen J Gildea J Felder RA Jose PA et al MiR-217 mediates the protective effects of the dopamine D2 receptor on fibrosis in human renal proximal tubule cells Hypertension 2015 May65(5)1118-25 PubMed PMID 25801876 Pubmed Central PMCID 4393363Novel in vitro studies using human derived proximal tubular cells illustrating the role of micro-RNA 217 in mediating the protective effects of the D2 receptor41 Nurnberger A Rabiger M Mack A Diaz J Sokoloff P Muhlbauer B et al Subapical localization of the dopamine D3 receptor in proximal tubules of the rat kidney The journal of histochemistry and cytochemistry official journal of the Histochemistry Society 2004 Dec52(12)1647-55 PubMed PMID 1555721942 Yang S Han Y Zheng S Kou X Asico LD Huang H et al Enhanced Natriuresis and Diuresis in Wistar Rats Caused by the Costimulation of Renal Dopamine D3 and Angiotensin II Type 2 Receptors American journal of hypertension 2015 Oct28(10)1267-76 PubMed PMID 25770092Studies in both rodents an in vitro demonstrating the additive effects of D3R and angiotensin receptor agonism on salt and water excretion43 Chen K Deng K Wang X Wang Z Zheng S Ren H et al Activation of D4 dopamine receptor decreases angiotensin II type 1 receptor expression in rat renal proximal tubule cells Hypertension 2015 Jan65(1)153-60 PubMed PMID 25368031 Pubmed Central PMCID 4268176

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Studies in tubular cells and rats demonstrating interactions between D4R expression and activation and AT1 receptor activity44 Bek MJ Wang X Asico LD Jones JE Zheng S Li X et al Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice Hypertension 2006 Feb47(2)288-95 PubMed PMID 1638053745 Yang S Yao B Zhou Y Yin H Zhang MZ Harris RC Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury Am J Physiol Renal Physiol 2012 Mar 15302(6)F742-9 PubMed PMID 22169008 Pubmed Central PMCID 331131446 Zhang MZ Harris RC Antihypertensive mechanisms of intra-renal dopamine Curr Opin Nephrol Hypertens 2015 Mar24(2)117-22 PubMed PMID 25594544 Pubmed Central PMCID 4651846A comprehensive examination of the roles of dopamine on blood pressure regulation within the kidney47 Clark BA Rosa RM Epstein FH Young JB Landsberg L Altered dopaminergic responses in hypertension Hypertension 1992 Jun19(6 Pt 1)589-94 PubMed PMID 159245348 Yatabe J Yatabe MS Yoneda M Felder RA Jose PA Sanada H Hypertension-Related Gene Polymorphisms of G-Protein-Coupled Receptor Kinase 4 Are Associated with NT-proBNP Concentration in Normotensive Healthy Adults International journal of hypertension 20122012806810 PubMed PMID 22518293 Pubmed Central PMCID 329621449 Rayner B Ramesar R Steyn K Levitt N Lombard C Charlton K G-protein-coupled receptor kinase 4 polymorphisms predict blood pressure response to dietary modification in Black patients with mild-to-moderate hypertension Journal of human hypertension 2012 May26(5)334-9 PubMed PMID 2154408650 Wang X Escano CS Asico L Jones JE Barte A Lau YS et al Upregulation of renal D5 dopamine receptor ameliorates the hypertension in D3 dopamine receptor-deficient mice Hypertension 2013 Aug62(2)295-301 PubMed PMID 23753418 Pubmed Central PMCID 378157951 Luippold G Zimmermann C Mai M Kloor D Starck D Gross G et al Dopamine D(3) receptors and salt-dependent hypertension J Am Soc Nephrol 2001 Nov12(11)2272-9 PubMed PMID 1167540352 Carey RM The intrarenal renin-angiotensin system in hypertension Advances in chronic kidney disease 2015 May22(3)204-10 PubMed PMID 25908469A review of the current literature studying the renal actions of the renin-angiotensin system and their effects on blood pressure53 Crowley SD Gurley SB Herrera MJ Ruiz P Griffiths R Kumar AP et al Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney Proc Natl Acad Sci U S A 2006 Nov 21103(47)17985-90 PubMed PMID 17090678 Pubmed Central PMCID 169385954 Macconi D Remuzzi G Benigni A Key fibrogenic mediators old players Renin-angiotensin system Kidney international supplements 2014 Nov4(1)58-64 PubMed PMID 26312151 Pubmed Central PMCID 4536968

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55 Schrimpf C Teebken OE Wilhelmi M Duffield JS The role of pericyte detachment in vascular rarefaction Journal of vascular research 201451(4)247-58 PubMed PMID 25195856 Pubmed Central PMCID 447641156 Weigert C Brodbeck K Klopfer K Haring HU Schleicher ED Angiotensin II induces human TGF-beta 1 promoter activation similarity to hyperglycaemia Diabetologia 2002 Jun45(6)890-8 PubMed PMID 1210773457 Abbate M Zoja C Rottoli D Corna D Tomasoni S Remuzzi G Proximal tubular cells promote fibrogenesis by TGF-beta1-mediated induction of peritubular myofibroblasts Kidney Int 2002 Jun61(6)2066-77 PubMed PMID 1202844758 Gagliardini E Corna D Zoja C Sangalli F Carrara F Rossi M et al Unlike each drug alone lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes Am J Physiol Renal Physiol 2009 Nov297(5)F1448-56 PubMed PMID 1967518159 Rodriguez-Romo R Benitez K Barrera-Chimal J Perez-Villalva R Gomez A Aguilar-Leon D et al AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease Kidney Int 2015 Oct 28 PubMed PMID 26509589An interesting observation on the role of systemic AT1 receptor blockade on preventing longer term renal fibrosis after experimental ischaemia-reperfusion injury60 Campbell DJ Kladis A Duncan AM Bradykinin peptides in kidney blood and other tissues of the rat Hypertension 1993 Feb21(2)155-65 PubMed PMID 842877861 Mamenko M Zaika O Pochynyuk O Direct regulation of ENaC by bradykinin in the distal nephron Implications for renal sodium handling Curr Opin Nephrol Hypertens 2014 Mar23(2)122-9 PubMed PMID 24378775 Pubmed Central PMCID 4114036A detailed summary of recent advances in our understanding of the role of bradykinin in sodium handling within the kidney62 Bulut OP Dipp S El-Dahr S Ontogeny of bradykinin B1 receptors in the mouse kidney Pediatric research 2009 Nov66(5)519-23 PubMed PMID 19581823 Pubmed Central PMCID 278339863 Kayashima Y Smithies O Kakoki M The kallikrein-kinin system and oxidative stress Curr Opin Nephrol Hypertens 2012 Jan21(1)92-6 PubMed PMID 22048723 Pubmed Central PMCID 365772664 Regoli D Plante GE Gobeil F Jr Impact of kinins in the treatment of cardiovascular diseases Pharmacology amp therapeutics 2012 Jul135(1)94-111 PubMed PMID 2253766465 Kakoki M Sullivan KA Backus C Hayes JM Oh SS Hua K et al Lack of both bradykinin B1 and B2 receptors enhances nephropathy neuropathy and bone mineral loss in Akita diabetic mice Proc Natl Acad Sci U S A 2010 Jun 1107(22)10190-5 PubMed PMID 20479236 Pubmed Central PMCID 289047566 McFarlane SI Kumar A Sowers JR Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease The American journal of cardiology 2003 Jun 1991(12A)30H-7H PubMed PMID 12818733

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67 Katori M Majima M Renal (tissue) kallikrein-kinin system in the kidney and novel potential drugs for salt-sensitive hypertension Progress in drug research Fortschritte der Arzneimittelforschung Progres des recherches pharmaceutiques 20146959-109 PubMed PMID 2513004068 Kaplan AP Bradykinin-mediated diseases Chemical immunology and allergy 2014100140-7 PubMed PMID 2492539469 Estrela GR Wasinski F Almeida DC Amano MT Castoldi A Dias CC et al Kinin B1 receptor deficiency attenuates cisplatin-induced acute kidney injury by modulating immune cell migration Journal of molecular medicine 2014 Apr92(4)399-409 PubMed PMID 2435726370 Estrela GR Wasinski F Bacurau RF Malheiros DM Camara NO Araujo RC Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury International immunopharmacology 2014 Sep22(1)115-9 PubMed PMID 24975837These two papers above use both pharmacological blockade and genetic ablation to demonstrate protected phenotypes in mice lacking kinin B1 and B2 receptors when challenged with cisplatin to generate acute kidney injury71 Huart A Klein J Gonzalez J Buffin-Meyer B Neau E Delage C et al Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy but is not additive Frontiers in pharmacology 201568 PubMed PMID 25698969 Pubmed Central PMCID 431358772 Imig JD Epoxyeicosatrienoic acids hypertension and kidney injury Hypertension 2015 Mar65(3)476-82 PubMed PMID 25583156 Pubmed Central PMCID 432658573 Schnermann J Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback a quantitative assessment Annual review of physiology 201577301-22 PubMed PMID 25668021A comprehensive and up to date summary of the multiple pathways now recognized to contribute to tubuloglomerular feedback74 Harris RC Zhang MZ Cyclooxygenase metabolites in the kidney Comprehensive Physiology 2011 Oct1(4)1729-58 PubMed PMID 2373368775 Eskildsen MP Hansen PB Stubbe J Toft A Walter S Marcussen N et al Prostaglandin I2 and prostaglandin E2 modulate human intrarenal artery contractility through prostaglandin E2-EP4 prostacyclin-IP and thromboxane A2-TP receptors Hypertension 2014 Sep64(3)551-6 PubMed PMID 24914192Studies in ex vivo human arteries demonstrating effects of prostaglandins and their receptors on arterial contractility- a finding of relevance to disease states and for drug toxicity76 Curiel RV Katz JD Mitigating the cardiovascular and renal effects of NSAIDs Pain medicine 2013 Dec14 Suppl 1S23-8 PubMed PMID 2425599777 Jia Z Sun Y Liu S Liu Y Yang T COX-2 but not mPGES-1 contributes to renal PGE2 induction and diabetic proteinuria in mice with type-1 diabetes PLoS One 20149(7)e93182 PubMed PMID 24984018 Pubmed Central PMCID 4077725

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78 Rubattu S Mennuni S Testa M Mennuni M Pierelli G Pagliaro B et al Pathogenesis of chronic cardiorenal syndrome is there a role for oxidative stress Int J Mol Sci 201314(11)23011-32 PubMed PMID 24264044 Pubmed Central PMCID 385610379 Rao R Zhang MZ Zhao M Cai H Harris RC Breyer MD et al Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria Am J Physiol Renal Physiol 2005 Apr288(4)F642-9 PubMed PMID 1558566980 Jia Z Zhang Y Ding G Heiney KM Huang S Zhang A Role of COX-2mPGES-1prostaglandin E2 cascade in kidney injury Mediators of inflammation 20152015147894 PubMed PMID 25729216 Pubmed Central PMCID 433332481 Cherney DZ Miller JA Scholey JW Bradley TJ Slorach C Curtis JR et al The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes Diabetes 2008 Mar57(3)688-95 PubMed PMID 1808378182 Srivastava T Alon US Cudmore PA Tarakji B Kats A Garola RE et al Cyclooxygenase-2 prostaglandin E2 and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney Am J Physiol Renal Physiol 2014 Dec 15307(12)F1323-33 PubMed PMID 2523431083 Yang L Besschetnova TY Brooks CR Shah JV Bonventre JV Epithelial cell cycle arrest in G2M mediates kidney fibrosis after injury Nature medicine 2010 May16(5)535-43 1p following 143 PubMed PMID 20436483 Epub 20100504 eng84 Tang J Liu N Tolbert E Ponnusamy M Ma L Gong R et al Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury Am J Pathol 2013 Jul183(1)160-72 PubMed PMID 23684791 Pubmed Central PMCID 370274785 Cianciolo Cosentino C Skrypnyk NI Brilli LL Chiba T Novitskaya T Woods C et al Histone Deacetylase Inhibitor Enhances Recovery after AKI J Am Soc Nephrol 2013 May24(6)943-53 PubMed PMID 23620402 Pubmed Central PMCID 3665399 Epub 20130427 eng86 Wu CF Chiang WC Lai CF Chang FC Chen YT Chou YH et al Transforming growth factor beta-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis Am J Pathol 2013 Jan182(1)118-31 PubMed PMID 23142380 Pubmed Central PMCID 353802887 Yang H Fogo AB Cell senescence in the aging kidney J Am Soc Nephrol 2010 Sep21(9)1436-9 PubMed PMID 20705707 Epub 20100814 eng88 Baker DJ Wijshake T Tchkonia T Lebrasseur NK Childs BG van de Sluis B et al Clearance of p16(Ink4a)-positive senescent cells delays ageing-associated disorders Nature 2011 Nov 2 PubMed PMID 22048312 Epub 20111104 Eng89 Grgic I Campanholle G Bijol V Wang C Sabbisetti VS Ichimura T et al Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis Kidney Int 2012 Jul82(2)172-83 PubMed PMID 22437410 Epub 20120323 eng90 Venkatachalam MA Weinberg JM Kriz W Bidani AK Failed Tubule Recovery AKI-CKD Transition and Kidney Disease Progression J Am Soc

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Nephrol 2015 Aug26(8)1765-76 PubMed PMID 25810494 Pubmed Central PMCID 452018191 Lan R Geng H Polichnowski AJ Singha PK Saikumar P McEwen DG et al PTEN loss defines a TGF-beta-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis Am J Physiol Renal Physiol 2012 May 1302(9)F1210-23 PubMed PMID 22301622 Pubmed Central PMCID 336217792 Komlosi P Bell PD Zhang ZR Tubuloglomerular feedback mechanisms in nephron segments beyond the macula densa Curr Opin Nephrol Hypertens 2009 Jan18(1)57-62 PubMed PMID 1907769093 Singh P Thomson SC Renal homeostasis and tubuloglomerular feedback Curr Opin Nephrol Hypertens 2010 Jan19(1)59-64 PubMed PMID 1986494894 Bell PD Reddington M Intracellular calcium in the transmission of tubuloglomerular feedback signals The American journal of physiology 1983 Sep245(3)F295-302 PubMed PMID 641256395 Bell PD Navar LG Cytoplasmic calcium in the mediation of macula densa tubulo-glomerular feedback responses Science 1982 Feb 5215(4533)670-3 PubMed PMID 680003496 Schnermann J Briggs JP Tubuloglomerular feedback mechanistic insights from gene-manipulated mice Kidney Int 2008 Aug74(4)418-26 PubMed PMID 18418352 Pubmed Central PMCID 256292797 Peti-Peterdi J Kidokoro K Riquier-Brison A Novel in vivo techniques to visualize kidney anatomy and function Kidney Int 2015 Jul88(1)44-51 PubMed PMID 25738253 Pubmed Central PMCID 4490063This review summarises recent advances in the use of intravital imaging using multi-photon microscopy and genetically coded fluorescent markers to allow serial observation of signaling pathways and cellular interactions within structures such as the mammalian glomerulus and juxtaglomerular apparatus98 Singh P Deng A Blantz RC Thomson SC Unexpected effect of angiotensin AT1 receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy Am J Physiol Renal Physiol 2009 May296(5)F1158-65 PubMed PMID 19211684 Pubmed Central PMCID 268137099 Liu R Persson AE Simultaneous changes of cell volume and cytosolic calcium concentration in macula densa cells caused by alterations of luminal NaCl concentration The Journal of physiology 2005 Mar 15563(Pt 3)895-901 PubMed PMID 15661823 Pubmed Central PMCID 1665624100 Bankir L Roussel R Bouby N Protein- and diabetes-induced glomerular hyperfiltration role of glucagon vasopressin and urea Am J Physiol Renal Physiol 2015 Jul 1309(1)F2-23 PubMed PMID 25925260101 Cherney DZ Perkins BA Soleymanlou N Maione M Lai V Lee A et al Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus Circulation 2014 Feb 4129(5)587-97 PubMed PMID 24334175102 Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S et al Empagliflozin Cardiovascular Outcomes and Mortality in Type 2 Diabetes The New England journal of medicine 2015 Nov 26373(22)2117-28 PubMed PMID 26378978

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This important clinical study demonstrates reduced total mortality and improved cardiovascular outcomes in diabetic patients receiving empagliflozin This is an exciting demonstation of the potential for novel therapies targeting the pathways described in this review to improve patient outcome

34

Abstract

The kidney mediates the excretion or conservation of water and electrolytes in

the face of changing fluid and salt intake and losses To ultrafilter and

reabsorb the exact quantities of free water and salts to maintain euvolemia a

range of endocrine paracrine and hormonal signaling systems have evolved

linking the tubules capillaries glomeruli arterioles and other intrinsic cells of

the kidney This review addresses the paracrine signals recognized to

mediate communication between adjacent and distant tubular cells of each

nephron and mechanisms by which tubules feedback and influence

glomerular function Our current understanding of pathway functions in health

and disease is reviewed as are future therapeutic options to protect the

healthy and injured kidney

Key words kidney tubule epithelial cell tubuloglomerular feedback hypertension fibrosis

Key points1 Multiple molecules are recognized to facilitate tubule to tubule

signalling within the kidney

2 Paracrine agents also have actions as vasoconstrictors or vasodilators

of the renal vasculature

3 ATP ATII bradykinin carbon monoxide superoxide and prostaglandin

derivatives mediate feedback at the macula densa from tubule to

glomerulus

4 Recent work has demonstrated pathogenic roles for signaling from

senescent or growth arrested tubular cells in aging and renal disease

2




















the membrane (7)




3













II(11)









4








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5













Nitric Oxide










6














Dopamine




segments (32)

7























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Angiotension II






9




fibrocytes (55)












Bradykinin








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Prostaglandins





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Conclusions






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changes in GFR

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the membrane (7)




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II(11)









4








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Nitric Oxide










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7























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Angiotension II






9




fibrocytes (55)












Bradykinin








10



















Prostaglandins





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Conclusions






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II(11)









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Prostaglandins





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Conclusions






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Endothelin-1















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Nitric Oxide










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Conclusions






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Dopamine




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Conclusions






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Angiotension II






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· web viewprovide negative feedback control in response to increased avp-induced osmotic water...

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