view - nephrology dialysis transplantation

Editorial Review

Treatment targets in renal fibrosis

Peter Boor1,2, Katarına Sebekova2, Tammo Ostendorf1 and Jurgen Floege1

1Division of Nephrology, RWTH University of Aachen, Aachen, Germany and 2Department of Clinical and ExperimentalPharmacotherapy, Slovak Medical University, Bratislava, Slovakia

Keywords: animal models; kidney scarring;progressive renal disease; treatment options

Introduction

Renal fibrosis is the principal process underlying theprogression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). It is a relatively uniformresponse involving glomerulosclerosis, tubulointersti-tial fibrosis and changes in renal vasculature (loss ofglomerular and peritubular capillaries) (Figure 1). Ofthese, tubulointerstitial fibrosis has evolved as the mostconsistent predictor of an irreversible loss of renalfunction and progression to ESRD [1].

Mechanisms contributing to tubulointerstitial injuryand tubular atrophy include glomerular proteinuria,chronic hypoxia, misdirected glomerular ultrafiltra-tion, tubular protein leakage and direct toxic insults ofe.g. drugs (reviewed in detail elsewhere [1–6]) . Director indirect tubulointerstitial injury via oxidative stressand various effector molecules trigger cellularresponses like (i) tubular epithelial cell (TEC) apopto-sis, (ii) activation of fibroblasts and their phenotypicswitch to myofibroblasts, (iii) influx and/or prolifera-tion of lymphocytes/macrophages, fibrocytes (thecirculating fibroblast precursors), fibroblasts as wellas (iv) epithelial-to-mesenchymal transition (EMT)of TECs.

Renal fibrosis provides an excellent treatment target,since a large variety of pathophysiologically distinctdiseases converge finally into this single process.However, we still do not have effective therapies, nordoes such a therapy exist in most other types of organfibrosis. Why? As part of the vital repair process, theregulation and redundancy in this system must behighly effective. The consequence is an amazinglycomplicated process that involves many cell typesand mediators [1,2,4,5,7]. Not unexpectedly, mono-therapeutic approaches, or even a combination of

therapies, fail to completely stop the progression ofrenal fibrosis [8–10]. In addition, not all combinationtherapies can be additive [11].

When identifying new targets or validating potentialtherapeutic options, we are confronted with severalproblems:

� Rodent models often do not fully mimic the clinicalsituation. Apart from the obvious species differ-ences, it is often difficult to distinguish whether thetested approach truly affected the phase of inter-stitial fibrosis or whether it ameliorated the under-lying primary renal injury to an extent that haltedthe progression. This problem is particularly rele-vant to the present review.

� Few approaches have been validated in multiplemodels.

� In the experimental situation, treatment is rarelystarted at a time point of established fibrosis(Table 1).

� Different parameters and techniques are used forthe evaluation of fibrosis. Often histologicalchanges are evaluated by semi-quantitative scoringrather than objective quantitative parameters.Standardized consensus approaches are urgentlyrequired.

� Most studies compare intervention to no interven-tion rather than comparing different approachesamongst each other or in combination with oneanother.

In the following, we will first discuss antifibroticapproaches, that are clinically available or close tobeing so, and then discuss potential new targets infibrosis therapy (Table 2).

Renin–angiotensin–aldosterone (RAAS) andkallikrein–kinin system

Angiotensin-converting enzyme inhibitors (ACEI) andangiotensin II receptor type 1 blockers (ARB) areundisputedly the first line drugs in combating renalfibrosis. These drugs, however, are not able to halt theprogression completely and in some conditions, likearistocholic acid-induced renal fibrosis in rats, they are

Correspondence and offprint requests to: Peter Boor, MD, Divisionof Nephrology, RWTH University of Aachen, Pauwelsstr. 30,52074 Aachen, Germany. Email: [email protected]

Nephrol Dial Transplant (2007) 22: 3391–3407

doi:10.1093/ndt/gfm393

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not effective at all [12]. Combination therapy of ACEIand ARB [13] or high-dosage of ACEI [14] showpotential in experimental studies to arrest or evenregress renal fibrosis, at least in the early stages.

Kallikrein cleaves the precursor kininogen to theactive vasodilator kinin peptide, bradykinin, which

via its B2 receptors mediates protective effects inhypertension, renal injury and fibrosis [15,16]. Genedelivery of kallikrein ameliorated renal scarring with-out affecting the blood pressure [17], and even reversedestablished kidney fibrosis [18]. ACE is the sameenzyme as kininase II, which degrades active kinins.Thus, ACE inhibition leads to kinin accumulation,which may contribute to the beneficial effects of ACEI.

Aldosterone inhibition, e.g. with mineralocorticoidreceptor blockers (spironolacton, eplerenone), alsoshows beneficial effects in experimental as well as inclinical studies (reviewed in [19,20]).

Renin inhibitors (aliskiren, enalkiren, zalkiren) arepromising drugs for combating renal fibrosis as shownin severely hypertensive transgenic rats (dTGR)harbouring the human renin and angiotensinogengene [21]. Clinical effects on renal fibrosis remain tobe determined. The recently discovered receptor forrenin and prorenin [(P)RR – (pro)renin receptor] waslinked to glomerular fibrosis [22]. (P)RR blockersmight be even more potent than renin inhibitors, sincerenin inhibitors do not block renin or prorenin bindingto and activation of (P)RR [22].

Vasopeptidase inhibitors (e.g. AVE7688, omapatri-lat) block both ACE and neutral endopeptidase, whichresults in a more pronounced blood pressure decrease,as compared with ACEI. AVE7688 potently retardedrenal fibrosis in an animal model of Alport syndrome[23]. However, the higher incidence of angioedemawith omapatrilat as compared with ACEI has limitedclinical studies thus far.

Table 1. Examples of experimental studies that showed effective antifibrotic treatment aproaches in established secondary renal fibrosis

Experimental model Treatment Treatment duration(days after diseaseinduction)

Reducedtubulo-interstitialfibrosis (at day)

Effect onbloodpressure

Ref.

5/6 nephrectomy Enalapril via drinking water 56–84 84 Yes [14]5/6 nephrectomy MMF by daily gavage or/and losartan

via drinking water30–60 and 30–120 60, 120 Yes [47]

5/6 nephrectomy VEGF121 injections twice daily 28–56 56 No [190]5/6 nephrectomy Adenoviral delivery of DDAH

(ADMA degrading enzyme) comparedwith hydralazine

28–42 42 No [283]

Salt induced nephropathy inDahl salt-sensitive rats

Adenoviral delivery of human tissuekallikrein gene

56–70 70 Yes [18]

Spontaneously hypertensive rats Human recombinant relaxin infusion 280–294 294 Yes [82]Accelerated anti-GBM nephritis IL-1 receptor antagonist infusion 7–21 21 ND [110]Accelerated anti-GBM nephritis BMP-7 injection every other day 7–42, 14–42, 21–42

and 28–4242 ND [166]

Anti-GBM nephritis Anti-TNF-a Ab injection every other day 14–28 28 ND [123]Adriamycin nephropathy CCR1 antagonist injection every 8 h 14–42 42 ND [137]Progressive anti-Thy1.1 GN Anti-PDGF-D Ab single injections 17, 28, 35 100 No [204]Cyclosporin A nephropathy VEGF121 injections twice daily 45–59 66 Yes [191]

Only original studies cited in this review were included. Some models were not included in the table, namely those considered models ofprimary tubulointerstitial damage, i.e. UUO and Alport-mice. All studies using genetically modified animals were also not included, since thefactor is always up-regulated/absent prior to disease induction. We also excluded models of diabetes (e.g. streptozotocin-induced diabetes ordb/db mice), lupus (MRL/lpr mice or pristane-induced lupus) or of chronic allograft nephropathy, were it is not possible to discriminate,whether reduction of established fibrosis was due to amelioration of the underlying disease or the fibrosis itself.Ab, antibody; ADMA, asymmetric dimethylarginine; BMP-7, bone morphogenic protein-7; CCR, receptor for CC chemokines; DDAH,dimethylarginine dimethylaminohydrolase; IL-1, interleukin 1, MMF, mycophenolate mofetil; ND, not determined; PDGF, platelet-derivedgrowth factor; VEGF, vascular endothelial growth factor.

Fig. 1. Severe tubulointerstitial fibrosis in an experimental rat modelof progressive mesangioproliferative glomerulonephritis on day 100after disease induction. The renal cortical section stained withperiodic acid-Schiff (PAS) shows typical tubulointerstitial damage:accumulation of extracellular matrix (�), tubular atrophy (��) andinflammatory infiltrates (��). Glomerular damage is apparent asglomerulosclerosis (arrow) and proteinuria (double arrow).Magnification: 100�.

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Endothelin, sympathic nerve system

Endothelin, acting via its receptors ETA and ETB, is apotent vasoconstrictor and mediator of fibroticresponse [2,24–26]. Although the dual inhibitor ofETA and ETB bosentan is in clinical use, its benefitsvs side effects (mainly hepatotoxicity and fluidretention) in CKD patients remain largely to beevaluated.

Blockade of sympathic nerve activity withmoxonidine reduced the progression of fibrosis in

5/6-nephrectomized rats without affecting blood pres-sure [27,28]. Selective a and b blockers in subantihy-pertensive dosages also ameliorated the developmentof renal fibrosis [29,30]. In cyclosporine-induced renaldamage, however, kidney denervation had no effect onthe development of fibrosis [31].

Environmental factors and metabolic syndrome

Smoking accelerates progression of kidney diseases,in part through blood pressure-mediated effects [32],

Table 2. Summary of reviewed targets and/or compounds for treatment of renal fibrotic disease

Target group Therapeutic target and/or approach Ref.

Renin–angiotensin–aldosterone system ACE (ACEI), Ang II R 1 (ARB), aldosterone (aldosteroneantagonists), ACE þ neutral endopeptidase(vasopeptidase inhibitors), renin (renin inhibitors,(P)RR antagonist)

[12–14,19–23]

Kallikrein–kinin system kallikrein–kinin–B2 receptors; kininase II [15–18]Endothelin ETA and ETB (dual inhibitor bosentan) [24–26]Sympathic nerve system � and � blockers, moxonidine [27–30]Environmental factors cessation of smoking, stress, caffeine intake, infections, heavy metals [32–36]Obesity, hypercholesterolaemia diet, statins [37–46]Immunosupressants MMF, rapamycin, FTY720, dexamethasone [47–56]ECM turnover

and compositionMMP-1, MMP-2, TIMPs-1, ADAM-19, ADAM-17, ADAMTS-1,

tissue transglutaminase, integrins (a1b1, aVb6), ILK, relaxin(relaxin), trypsinþbromelainþrutosid, pirfenidone

[58–65,76–83,85–92,94,95]

Fibrinolytic system PAI-1, tPA, plasminogen, uPAR [66–75]Complement system C5 (anti-C5 Ab), C5b-9 (CD59), C5a (C5aR antagonist), Crry [96–108]Cytokines IL-1 (IL-1 receptor antagonist), IL-4, IL-8, IL-10 (anti-IL-10 Ab),

IFN-g (IFN-�), IFN-a (IFN-�), TNF-a (anti-TNF-�-Ab)[109–115,

117–123,280]Chemokines MCP-1/CCR2, RANTES/CCR1, M-CSF, osteopontin, CX3CR1,

SLC/CCR7 (chemokine receptor antagonists)[127–143]

TGF-b signalling TGF-b, Smad-7, Smad-3 (halofuginone), Snail, Ski, SnoN, ALK5,decorin

[149–161,164,165]

TGF-b antagonists BMP-7, USAG-1, KCP [166–172,174,175]Other growth factors PDGF (see Table 3), HGF, CTGF (Anti-CTGF Ab), FGF-1, FGF-2,

VEGF (anti-VEGF-Ab), EGFR (anti-EGFR-Ab)[176–178,180,183–189,

192–197,212–218]Nitric oxide L-arginine, iNOS, eNOS, sGC, PDE (PDE antagonist pentoxifiline),

PDE-4, PDE-5 (PDE-5 antagonist sildenafil), NO-donors[219–232]

Intracellular transduction cascades NF-kB (curcumin), Rho/ROCK (Rho inhibitors), p38 MAPK(p38 MAPK inhibitors), JNK, PKC-b, PI3Kg (PI3K� inhibitors),transcription factor Sp1, various tyrosin kinase inhibitors

[146,161–163,233–240,273–277,281]

Various stem cells, mast cells, B-cells, selectins, AGEs, AOPPs, PPARg(glitazones), ADMA (DDAH), tranilast, 1,25-dihydroxyvitamin D,paracalcitol, retinoid receptor agonist isotretinoin, erythropoietin,polyunsaturated fatty acids, thromboxane receptor antagonistterutroban, N-acetyl-cysteine

[241,243–272,278,279,282,283]

Treatment options already available or currently being tested in humans are in italics. Intracellular transduction cascades are discussedin various parts of the text.Ab, antibody; ACE, angiotensine-converting enzyme; ACEI, ACE inhibitors; ADAM, a disintegrin and metalloprotease domain; ADAMTS,ADAM with thrombospondin motifs; ADMA, asymmetric dimethylarginine; AGE, advanced glycation end-product; ALK5, TGF-b1receptor kinase; Ang II, angiotensin II; Ang II R 1, Ang II receptor 1, AOPP, advanced oxidation protein product; ARB, angiotensin-receptor blocker; B2 receptors, bradykinine B2 receptors; BMP-7, bone morphogenic protein-7; C5a, complement component 5a; C5aR,receptor for C5a (CD88); C5b-9, membrane attack complex; CCL, CC chemokine; CCR, receptor for CC chemokines; CD59, membrane-bound complement regulatory protein; Crry, complement receptor-related protein; CTGF, connective tissue growth factor (CCN2);CX3CR1, fractalkine receptor 1; DDAH - dimethylarginine dimethylaminohydrolase; ECM, extracellular matrix; EGFR, epidermal growthfactor receptor; ETA, B, endothelin receptors A and B; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IFN, interferon; IL,interleukin; ILK, integrin linked kinase; JNK, c-Jun amino-terminal kinase; KCP, kielin/chordin-like protein; MCP-1, monocytechemoattractant protein (CCL2); M-CSF, macrophage-colony stimulating factor; MMF, mycophenolate mofetil; MMP, matrixmetalloproteinase; NF-kB, nuclear factor kB; NOS, nitric oxide synthase; p38 MAPK, p38 mitogen-activated protein kinase; PAI-1,plasminogen-activator inhibitor-1; PDE, phosphodiesterase; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3Kg,phosphatidyl-inositol-3-kinase-g; PKC-b, protein kinase C-b; PPARg, peroxisome proliferator-activated receptor-g;(P)RR, (pro)reninreceptor; RANTES, regulated on activation, normal T-cell expressed and secreted (CCL5); ROCK, Rho-kinase; sGC, soluble guanylatecyclase; Ski, Sloan-Kettering Institute proto-oncogene; SLC, secondary lymphoid tissue chemokine (CCL21); SnoN, Ski-related novel gene;TGF-b, transforming growth factor-b; TIMP, tissue inhibitor of MMPs; TNF, tumor necrosis factor; tPA, tissue-type plasminogen activator;uPA, urokinase plasminogen activator; uPAR, uPA receptor; USAG-1, uterine sensitization-associated gene 1; VEGF, vascular endothelialgrowth factor.

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but at least in experimental situations, also via apossible profibrotic effect [33,34]. Another indepen-dent factor that leads to progression of kidney diseaseis obesity [36]. Various pathways, including increasedmetabolic demands on the kidney, hyperinsulinaemiaor leptin overproduction, were shown to induce orpromote kidney scarring in obesity [37–40]. Diet-induced hypercholesterolaemia in rodents or pigsresulted in renal fibrosis, which was reversible bylipid-lowering dietary interventions [41,42]. Severalexperimental studies demonstrated the protectiveeffect of statins on kidney scarring, which may relateto their lipid-lowering but also to their anti-inflamma-tory actions [43–45]. First clinical data confirmed therenoprotective effects of statins [46] and large trials inCKD patients are underway.

Immunosuppressive agents

Mycophenolate mofetil (MMF) ameliorated fibrosis invarious experimental models [47–50]. These effectswere comparable, but not additive, with those ofenalapril or lisinopril [48,49]. Confirmatory data intransplanted patients has recently emerged [51].Rapamycin attenuated renal fibrosis in patients withkidney transplantation [52] and in unilateral ureteralobstruction (UUO) in rats [53]. Dexamethasonereduced fibrosis in renin transgenic rats similiarly toMMF [55], but failed to reduce fibrosis in mercuricchloride-treated rats, whereas tacrolimus was effectivein the latter [56].

Turnover and composition of the extracellular matrix

Matrix metalloproteinases (MMPs) were initiallythought to be beneficial in renal fibrosis, given thatthey degrade extracellular matrix (ECM) proteins.Recent data suggest that their role in renal scarringmay be much more complex [57] (Figure 2). In renalfibrosis, local delivery of MMP-1 reduced collagencontent in streptozotocin-induced diabetic nephropa-thy in rats [58]. On the other hand, tubular MMP-2overexpression in mice induced renal fibrosis [59] andselective pharmacological MMP-2 inhibition increasedfibrosis in UUO [60].

Tissue inhibitors of matrix metalloproteinases(TIMP-1 to -4) are natural MMP inhibitors. GeneticTIMP-1 deletion in mice had no influence on experi-mental kidney fibrosis [61,62], whereas overexpressionof TIMP-1 increased age-related fibrosis [63].

Membrane-bound ‘a disintegrin and metallopro-tease domain’ proteases (ADAMS) and secreted‘ADAM with thrombospondin motifs’ proteases(ADAMTS) are two other important families ofproteases (containing more than 50 members).ADAM-19 is abundant in fibrotic renal lesions inhuman biopsies [64]. ADAMTS-1-deficient miceexhibited kidney fibrosis in addition to renalmalformations [65].

Some proteases of the fibrinolytic pathway, i.e.plasminogen activator inhibitor-1 (PAI-1) [66–69],tissue-type plasminogen activator (tPA) [70,71] andplasminogen [72,73] are important profibrotic factors.However, in anti-glomerular basement membrane(anti-GBM) nephritis, all three factors proved to beantifibrotic, which may relate to their involvement inthe glomerular coagulation cascade, i.e. effects on theprimary renal disease as opposed to direct effects onrenal fibrosis [68,74,75]. Genetic urokinase-type plas-minogen activator (uPA) deficiency had no effect onfibrosis in UUO or anti-GBM nephritis; deficiency ofits receptor (uPAR) was antifibrotic in UUO but not inanti-GBM nephritis [66].

Tissue transglutaminase (Tg) stabilizes ECM byprotein cross-linking. This leads, for example, toresistance of such modified collagens to proteolyticdegradation by MMPs. Tissue Tg is upregulated andcorrelates closely with the severity of renal fibrosis inexperimental models and in humans [76,77]. At leastin vitro, inhibition of tissue TG reduced glucose-induced deposition of ECM proteins in renal proximaltubular epithelial cells [77].

Oral administration of a protease mixture (trypsinand bromelain with rutosid added as an antioxidant)reduced renal fibrosis in rats with 5/6-nephrectomy orGoldblatt hypertension independently of blood pres-sure [78,79]. Single proteases or their mixtures are usedin human medicine.

Relaxin is a small peptide hormone with potentantifibrotic activity in the kidney [80–82]. Its benefitmay derive in part from interference with transforminggrowth factor-b (TGF-b), a potent profibrotic cytokine[83]. Continuous subcutaneous infusion of relaxinshowed promising results in a phase II clinical trial inpatients with systemic sclerosis, but this effect was notconfirmed in a phase III trial [84].

Pirfenidone is a potent inhibitor of ECM accumula-tion as shown in several experimental models ofrenal damage, e.g. mesangioproliferative GN,5/6-nephrectomy or UUO [85,86], and in patientswith idiopathic pulmonary fibrosis and advanced liverfibrosis. We lack clinical data in renal patients.

Integrins are heterodimeric cell receptors for theECM. Integrin a1 chain-deficient mice developed moresevere glomerulosclerosis in adriamycin-induced renalinjury [87]. In contrast, genetic a1 chain-deficiency orantagonism of a1 chain reduced fibrosis in a mousemodel of Alport syndrome [88] and in rats withcrescentic GN [89] or mesangioproliferative GN [90].Integrin aVb6 binds to and activates latent TGF-b.Mice deficient of the b6 integrin chain exhibitedreduced fibrosis following UUO [91]. Deficiency ofb6 or aVb6-blocking antibodies also reduced fibrosisin Alport mice [92]. In contrast, genetic deficiency ofthe a8-chain did not contribute to glomerulosclerosisor fibrosis [93]. Outside-in signalling of integrinsinvolves, amongst other functions, activation of theintegrin-linked kinase (ILK) pathway. ILK wassuggested to participate in the development of renalfibrosis [94,95].

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Collectively these data suggest that some systems,such as MMPs, the fibrinolytic pathway and integrins,may be difficult to interfere with clinically, given theircomplex nature, their redundancy and their sometimesopposing biological effects. However, some attractivetherapeutic options such as Tg- antagonists are startingto emerge.

Complement system

The terminal complex of complement, C5b-9 (ormembrane attack complex—MAC) is formed at sitesof tubulointerstitial injury [1], its depletion in experi-mental nephropathy reduces proteinuria [96] andinhibition of MAC formation in proteinuric animal

models ameliorated tubulointerstitial injury [1,97–99].However, genetic C6 deficiency, which precludesMAC formation, did not affect the severity of non-proteinuric models of tubulointerstitial injury [100],suggesting that MAC mediates tubulointerstitialdamage in proteinuric renal diseases only [100].

Besides C5b-9, complement C5 and in particularC5a may also become a target in renal fibrosis: inexperimental murine immune-complex GN, geneticdeficiency of the C5a receptor (C5aR) led to reducedinterstitial cell infiltration and tubulointerstitialdamage without affecting the glomerular injury. Thispointed to a role of the anaphylatoxin C5a, a smallpeptide released from C5, in tubulointerstitial injury[105]. In the mouse UUO model, genetic C5 deficiencyor pharmacological inhibition of C5aR potently

Fig. 2. Complexity of MMP driven proteolysis. Each of the 23 human and 24 murine MMPs can be regulated at different levels, ranging fromRNA processing to activation of inactive MMPs (zymogens) and/or degradation of active MMPs by other proteases (e.g. other MMPs). Thebroad range of the MMPs targets resulting in a diversity of biological functions adds another level of complexity to this protease system. Withrespect to fibrosis, it seems obvious, that MMPs should not be viewed as merely ECM degrading ‘anti-fibrotic’ molecules. Adapted andmodified from [285]. ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; FGF,fibroblast growth factor; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; TGF-b, transforming growth factor-b; TIMP, tissue inhibitor of MMPs; TNF-a, tumournecrosis factor-a; VEGF, vascular endothelial growth factor.


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reduced tubulointerstitial fibrosis [106]. C5aR defi-ciency or antagonism also attenuated the course oflupus nephritis in mice [107,108]. C5aR antagonistsand anti-C5 antibodies (eculizumab) were/are beingevaluated in clinical trials.

Complement regulatory proteins such as Crry, whichinhibits C3 activation, or CD59, which inhibits C5b-9formation, may also be of interest: Local deficiencyof Crry aggravated tubular damage and fibrosis inpuromycin-induced nephropathy (PAN) and in modelsof renal transplantation [101,102]. Crry and CD59were equally therapeutic in PAN [103]. Treatment withCrry also decreased renal ECM accumulation inmurine lupus nephritis [104], but here, effects on theimmune system vs direct, antifibrotic effects aredifficult to distinguish.

Cytokines

Few data are available on the role of interleukins (IL)in renal fibrosis. One exception is IL-1b, whoseprofibrotic properties in experimental renal diseasehave been established [109–113]. Although an IL-1receptor antagonist (anakinra) is already in clinical use,it has not been tested so far in patients with renalfibrosis. In mice lacking the IL-8 receptor, whichmediates transepithelial migration, trapped neutrophilslead to tissue destruction and renal fibrosis afterexperimental pyelonephritis [114]. An antifibroticaction of IL-10 was described in 5/6-nephrectomizedrats [115]. IL-10 is also anti-inflammatory and anti-atherogenic and systemic treatment was well toleratedin psoriasis patients [116]. However, systemic treat-ment with IL-10 was ineffective in patients withrheumatoid arthritis or Crohn’s disease [116], unlesslocally delivered in the gut of Crohn’s patients. Thus,local delivery in renal patients could become a limitingfactor. It also should be stressed that in systemic lupuserythematosus IL-10 seems to be a harmful factor[116]. Early IL-4 administration in rats with crescenticGN diminished tubulointerstitial fibrosis in the latercourse of the disease [117]. Although IL-5, -6 and -13are involved in the pathogenesis of some renal diseases,no data currently exist on their role in renal scarring.

Interferon-g (IFN-g) has antifibrotic propertiesin vitro [118] and administration to 5/6-nephrectomizedrats decreased kidney fibrosis [119]. However, in ratswith mesangiopoliferative GN, IFN-g treatmentdecreased mesangial cell proliferation but not glomer-ular ECM accumulation [120]. IFN-a reduced intersti-tial fibrosis in carbon tetrachloride-inducednephrotoxicity [121]. Although IFN treatment long-term clinical therapy is feasible, the case for such treat-ment in renal fibrosis patients is not particularly strong.

Tumour necrosis factor-a (TNF-a) is a well-recognized promoter of fibrosis in the kidney[122–124]. Although anti-TNF-a antibodies arehighly effective in patients with rheumatoidarthritis, side effects such as serious infections andmalignancies [125], or increased mortality in patients

with chronic heart failure [126], may limit clinical trialsin renal fibrosis.

Chemokines

Several chemokines and their receptors were shownto act in a profibrotic manner, mainly via recruitmentof inflammatory cells into the tubulointerstitium [6].These profibrotic molecules include monocyte chemoa-tractant protein-1 (MCP-1/CCL2) and its receptorCCR2 [127–133], RANTES (CCL5) and its receptorCCR1 (but not CCR5) [134–137], macrophage-colonystimulating factor (M-CSF) [138], osteopontin[139–141] and fractalkine receptor 1 (CX3CR1) [142].The secondary lymphoid tissue chemokine(SLC/CCL21) and its receptor CCR7 have beenimplicated in the regulation of fibrocyte infiltrationof the renal interstitium and promotion of fibrosis[143]. Several problems render a translation of theseresults into clinical trials difficult [6]: (i) There areconsiderable species differences in the expression ofchemokines and their receptors. (ii) Although profi-brotic in most disease models, chemokines might bealso beneficial; e.g. lack of CCR1 or CCR2 wasantifibrotic in UUO but aggravated renal injury increscentic GN [144,145]. (iii) Chemokine receptorantagonists developed for clinical use, e.g. antagonistsof CCR2 and CCR5, cross-react with other closelyrelated G-protein-coupled receptors, resulting in insuf-ficient specificity in humans. An alternative approachcould be the inhibition of chemokine signalling viaphosphatidylinositol-3-kinase-g (PI3Kg). Indeed,a PI3Kg inhibitor ameliorated the severity of lupusnephritis in mice [146].

TGF-�, TGF-� signalling molecules, p38 MAPK,bone morphogenic protein-7 (BMP-7)

TGF-b, a central mediator of fibrosis, exerts itsbiological, in particular immunological, functions viacomplex signalling pathways [147]. In view of its potentaction as an endogenous immunosuppressant, com-plete blockade of TGF-b signalling could have seriousadverse consequences. Thus, TGF-b-deficient micedie of a multifocal inflammatory syndrome [148].However, the complexity of TGF-b regulation and itsdownstream pathways provide possibilities for morespecific treatment targets (e.g. BMP-7, HGF, CTGF,Smads) (Figure 3). It should be mentioned that whilemost of the research focuses on the TGF-b1 isoform,the other isoforms, b2 and b3, also have profibroticeffects on kidney cells [149].

Overexpression of Smad7, an inhibitory factor in theTGF-b signalling pathway, reduced renal fibrosis in5/6-nephrectomy and UUO [150–152]. Alternatively,genetic deletion of the agonistic signalling molecule,Smad3, protected kidneys from interstitial fibrosis[153,154]. The plant alkaloid halofuginone is aninhibitor of collagen I synthesis, recently shown toalso inhibit Smad3 [155]. Halofuginone was

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successfully used for topical treatment of fibrosis inpatients with scleroderma, had good tolerability afteroral administration and is currently being tested incancer patients. Snail is a transcription factor involvedin EMT and is strongly activated by TGF-b.Activation of Snail in adult transgenic mice inducedrenal fibrosis and Snail was found to be overexpressedin human fibrotic kidney [156]. Other targets in renalscarring might be the antifibrotic Smad co-repressors,Ski and SnoN [157,158]. Inhibition of the TGF-b1receptor kinase (ALK5) alone [159,160] or in combina-tion with inhibition of p38 mitogen-activated proteinkinase (MAPK) [161] ameliorated renal fibrosis.Inhibition of p38 MAPK also reduced fibrosis inUUO and unilateral kidney ischaemia–reperfusion[162,163], and p38 MAPK inhibitors are currentlytested in clinical trials in patients with inflammatory

diseases, e.g. asthma. Lack of decorin, a proteoglycaninvolved in ECM assembly and a TGF-b antagonist,elevated interstitial fibrosis in UUO [164] and deliveryof decorin by gene therapy prevented fibrosis inglomerulonephritic rats [165].

BMP-7 was shown to reduce (more potently thanenalapril) or even reverse renal interstitial fibrosis invarious experimental models [166–170]. Furthermore,treatment with BMP-7 had beneficial effects on renalosteodystrophy and reduced vascular calcification inuraemia [171,172]. However, in the protein overloadmodel in rats, treatment with BMP-7 protein showedno significant effects on renal fibrosis [173]. BMP-7therapy in patients has not yet been reportedbut the results of ongoing studies are eagerlyawaited. Kielin/chordin-like protein (KCP) and uterinesensitization-associated gene-1 (USAG-1) are an endo-genous BMP-7 agonist and antagonist, respectively.Mice lacking KCP were more susceptible to develop-ment of renal fibrosis [174], whereas mice lackingUSAG-1 were protected [175].

Hepatocyte growth factor (HGF) and connectivetissue growth factor (CTGF; CCN2)

HGF was shown to have antifibrotic properties indifferent animal models via inhibitory effects onSmad2/3 and activation of SnoN, which binds andinactivates Smad2 [176–179]. However, HGF over-expression or its glomerular ultrafiltration in diabeticnephropathy rats with proteinuria have also beenimplicated in the development of renal fibrosis[180,181]. The pro-carcinogenic HGF effects [182]raise safety concerns for clinical trials.

CTGF, a potent profibrotic molecule, is at least inpart a direct downstream mediator of TGF-b. Itdecreases vascular endothelial growth factor (VEGF)signalling, enhances signalling of several growthfactors [e.g. TGF-b itself, epidermal growth factor(EGF), platelet-derived growth factor (PDGF), basicfibroblast growth factor (bFGF)] and directly regulatescell functions (adhesion, migration, proliferation) viabinding to integrins and ECM [183,184]. CTGF isa direct mediator of profibrotic effects of AGEs,is up-regulated in humans with renal fibrosis and itsinhibition resulted in a potent reduction of fibrosisin experimental diabetic nephropathy, UUO and5/6-nephrectomy [183–188]. Anti-CTGF therapy isnow in clinical trials in diabetic nephropathy.

Vascular endothelial growth factor (VEGF)

VEGF is a potent angiogenic factor, which isalso involved in fibrosis [189]. In rats with 5/6-nephrectomy, cyclosporine nephropathy and throm-botic microangiopathy, administration of VEGF121

reduced fibrosis and renal damage [189–191].Consistent with this, VEGF antagonism acceleratedrenal damage in mice with progressive crescentic GN[192] and in rats with mesangioproliferative GN [193].

Fig. 3. TGF-b signalling and it modulation. Thesimplified scheme shows Smad signalling of TGF-b and BMP-7and mainly encompasses molecules discussed in the text. Differentmolecules modify extracellularly the activity of TGF-b or BMP-7(note: CTGF effects on BMP-4 have been shown, but its effects onBMP-7 signalling are less clear). TGF-b or BMP-7 binding to theirreceptors induces heteromeric receptor complexes with kinaseactivation (ALK5 and ALK3, respectively) that leads to recruitmentand phosphorylation of Smads (Smad2/3 and Smad1/5, respec-tively). These phospho-Smads (pSmad) form heteromers with Smad4and are transported to the nucleus where they regulate geneexpression. Antagonistic effects of BMP-7 on TGF-b signalling aredepicted in the example of collagen type I expression and onnuclear shuttling and phosphorylation of Smad3. Non-SmadTGF-b signalling, shown in the right side of the picture, can involveactivation of p38 MAPK, JNK and Rho. The modulationof TGF-b-induced gene transcription by Smad co-repressorsSki and SnoN in nucleus is also shown. Arrows indicatestimulatory effects and blunted lines inhibitory effects. ‘P’ standsfor phosphorylation.ALK3, BMPR-IA kinase; ALK5, TbRI kinase; BMP-7, bonemorphogenic protein-7; BMPR-IA, BMP receptor IA; BMP-RII,BMP receptor II; JNK, c-Jun amino-terminal kinase; KCP, kielin/chordin-like protein; p38 MAPK, p38 mitogen-activated proteinkinase; TbR, TGF-b1 receptor; TGF-b, transforming growthfactor-b; USAG-1, uterine sensitization-associated gene 1.


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However, the action of VEGF may depend on thebiological context, since, in contrast to the above data,a VEGF neutralizing antibody ameliorated early renalinjury, in particular glomerular hypertrophy, in5/6-nephrectomized rats, in mice fed with a high-protein diet and in rats with diabetic nephropathy[194–197]. Various anti-VEGF aproaches are approvedfor use in patients, and renal side effects includeproteinuria and hypertension [198]. Given the abovedata, the complexity of the VEGF system (five familymembers with alternative splicing, four differentreceptors) and potential adverse pro-angiogenic effectsof VEGF-therapy, it appears uncertain whether VEGFadministration or blockade will become a usefulapproach in patients with renal fibrosis.

Platelet-derived growth factor (PDGF)

PDGF is a key mediator of fibrosis in different organs,including the kidney (Table 3 and Figure 4). ThePDGF–B and –D isoforms mediate glomerular ECMaccumulation in GN [199]. Their main receptor, i.e.PDGFR-b (Figure 4), is upregulated in the fibrotictubulointerstitium [199]. PDGF-B also exerts itsprofibrotic effects in the tubulointerstitial compart-ment [200,201]. PDGF-D expression increases inobstructive uropathy in both humans and mice [202].In rats with progressive mesangioproliferative GN,treatment with PDGF-D-neutralizing antibody ame-liorated the early glomerular damage and the sub-sequent tubulointerstitial fibrosis [203]. Furthermore,this treatment prevented progression and fibrosis, evenif initiated at the stage of established tubulointerstitialdamage [204]. In a phase I clinical trial, a PDGF-D-neutralizing antibody had promising safety/tolerabilityprofile, pharmacodynamic properties and long half-life(Hahne et al., J Am Soc Nephrol 2005; 16: AbstractSA-PO1017).

The PDGFR-a ligand PDGF-C (Figure 4), alsoseems to be an important mediator of fibrogenic

stimuli. PDGF-C is expressed de novo in the fibroticinterstitium of rat and human kidneys [205,206] and itsspecific antagonism in the mouse UUO reduced fibroticchanges (Eitner et al., submitted for publication).

Imatinib (STI-571) is widely used in cancer therapyas a multi-kinase blocker of the c-abl, c-kit andPDGFR tyrosine kinases. Imatinib ameliorated renalfibrosis in UUO [207] and retarded the developmentof experimental diabetic [208] and chronic allograftnephropathy [209]. It remains uncertain whether thisbeneficial effect of imatinib was indeed mediated viareduction of PDGF signalling or whether it related toeffects on c-abl kinase [207]. In clinical studies, sideeffects of imatinib include effects on haematopoesis,heart [210] and bone [211].

Other growth factors

The role of basic fibroblast growth factor-2 (FGF-2)in renal fibrosis is well established, at least in vitro[212–214]. FGF-1 and its receptor were also identifiedin human interstitial fibrotic lesions [215]. Specificinterventions have not been performed in either casein renal fibrosis.

Inhibition of epidermal growth factor receptor(EGFR) is protective against the development offibrosis in models of hypertensive renal damage andrenal mass reduction [216,217]. Expression of adominant negative EGFR prevented renal lesionsinduced by chronic Ang II infusion [218].

Similarly protective in the above model were thegenetical deletion of TGF-a or pharmacologicalinhibition of its activating sheddase TACE(ADAM17) [218]. Anti-EGFR treatment is approvedfor treatment of some cancers.

Nitric oxide, NF-�B and Rho/Rho kinase

Enhanced production of nitric oxide (NO) followingL-arginine administration prevented progression of

Table 3. Experimental in vivo modulation of PDGF signalling in renal fibrosis

Target Experimental model Aproach Fibrosis Ref.

PDGF-A normal rat PDGF-A administration none [201]PDGF-B normal rat PDGF-B administration " [201]

normal mice Hepatic overexpression " [284]rat progressive anti-Thy1 GN Aptamer antagonist # [200]

PDGF-C UUO Antibody # unpub.UUO Knock-out mice # unpub.

PDGF-D normal mice Hepatic overexpression " [284]rat progressive anti-Thy1.1 GN Antibody # [203]rat progressive anti-Thy1.1 GN Antibody # [204]

PDGFR UUO Imatinib # [207]tyrosine diabetic nephropathy Imatinib # [208]kinase chronic allograft nephropathy Imatinib # [209]

Imatinib is a multikinase inhibitor and its effect might also be contributed to inhibition of other kinases, e.g. c-abl kinase (discussed in text).# decreased fibrosis; " induced fibrosis.GN, glomerulonephritis; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; unpub., unpublished data; UUO, unilateralureteral obstruction.

3398 P. Boor et al.

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renal fibrosis in several models [219–221] but acceler-ated it in mice with lupus nephritis [222] andadriamycin nephropathy [223]. In two differentmodels of non-immune progressive kidney damage,

pharmacological inhibitors of inducible NO synthase(NOS) [223] or endothelial NOS [224] reduced renalfibrosis. Studies in the UUO model using iNOS-deficient mice or using liposome-mediated iNOS genetransfer confirmed the protective role of iNOS[225,226], and genetic eNOS deficiency in mice led toprogressive focal kidney scarring [227]. A secondmessenger of NO, cGMP, is synthesized by solubleguanylate cyclase (sGC) and degraded by phospho-diesterases (PDE). Stimulation of sGC slowed fibrosisdevelopment in progressive mesangioproliferative GN[228]. The PDE-5 inhibitor, sildenafil, effectivelyprevented the developmet of fibrosis, but it wasineffective in reversing established lesions [229].Another PDE inhibitor, pentoxifiline, was antifibroticin UUO and, combined with an ACEI, after 5/6nephrectomy [230,231], but was less effective in ahead-to-head comparison with a compound stimulat-ing sGC [231]. In UUO, however, neither PDE-4inhibition nor an A2A adenosine receptor agonist wereable to reduce kidney damage [232].

Nuclear factor-kB (NF-kB) activation is a centralconvergence point of many proinflammatory pathwaysand a downstream effector of profibrotic moleculessuch as AGEs, the RAAS system or Smad7 [233].Reduced renal fibrosis was noted following inhibitionof NF-kB, e.g. with curcumin (diferuloylmethane)[233,234]. First clinical trials with curcumin in patientswith malignancies showed no dose-dependent toxicityand phase II trials are underway.

Signalling via the G protein Rho and its associatedRho-kinase (ROCK) has been linked with renalfibrosis using two Rho-kinase inhibitors, Y-27632and fasudil [235–238]. Both were already successfullyused in clinical trials in patients with cardiovasculardiseases [239]. Nevertheless, genetic deletion ofROCK1 had no effect on renal fibrosis in UUO[240]. The involvement of Rho/ROCK in human renaldisease is largely unkown.

Stem cells

Stem cells hold great promise in acute renal failure andpossibly even in chronic, fibrosing renal failure [241].Indeed, three recent studies showed a beneficial effectof bone marrow-derived cells in a mice model of Alportsyndrome [242–244]. However, very few studies haveso far addressed the latter situation, and the challengeis to prevent stem cells receiving profibrotic signalsfrom their environment and/or to prevent theirmaldifferentiation. Thus, it has recently been shownthat bone marrow-derived myofibroblasts will con-tribute to renal fibrosis following ischaemia reperfu-sion injury [245]; and we observed thatadministration of mesenchymal stem cells to ratswith progressive mesangioproliferative GN initiallyimproved acute renal failure, but in the long-term,these cells adopted an adipocyte-like phenotypein glomeruli and induced an intense fibroticresponse [246].

Fig. 4. Simplified scheme of PDGF signalling and its regulation.Only the main molecules relevant for this review are listed.PDGF -AA, -AB and -BB are secreted in an active form whereasPDGF -DD and -CC are activated extracellularly via proteolyticcleavage of CUB-domain by urokinase plasminogen activator (tPA)or tissue plasminogen activator (uPA), respectively. Binding ofPDGF isoforms results in autophosphorylation of the appropriatePDGF receptor. This subsequently leads to recruitment andactivation of downstream signalling pathways such as Jak/STAT,PI3K, PLC-g or MAPK, which via regulation of gene expressionmediate the biological functions of PDGF isoforms, e.g. prolifera-tion, chemotaxis, migration or ECM production. The signallingpathways depicted are common to all three PDGF receptors and thesignal transduction results in overlapping yet distinct biologicaleffects depending on the receptor and cell type (e.g. via differentbinding affinities of the signalling molecules to phosphorylatedreceptors). An example of a relevant profibrotic cross-talk is thecooperation of PDGF and integrin signalling. Binding of ECMcomponents (e.g. fibronectin, laminin) to integrins activatesoutside-in signalling via the focal adhesion kinase (FAK) pathwaythat enhances PDGF induced MAPK signalling. This results inenhanced cell proliferation and migration. Integrins also cooperatewith other receptors for growth factors and directly activatesignalling pathways such as PI3K, JNK and ILK. Various otherregulatory steps might be involved in PDGF-signalling in fibrosis,e.g. regulation of PDGF and PDGFR expression, PDGF degrada-tion or binding to non-signalling molecules (e.g. SPARC or heparin-sulphate proteoglycans). ECM, extracellular matrix; FAK, focaladhesion kinase; ILK, integrin linked kinase; JAK, Janus kinases;JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activatedprotein kinase; PDGF, platelet-derived growth factor; PDGFR,PDGF receptor; PI3K, phosphatidyl-inositol-3-kinase; PLC-g,phospholipase C-g; STAT, Signal transducers and activators oftranscription; tPA, tissue-type plasminogen activator; uPA, uroki-nase plasminogen activator.


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Other treatment targets and approaches

There is a number of targets that might be potentiallyeffective in treatment of renal fibrosis (Table 2). Someof them were already tested in several experimentaland/or small clinical studies, e.g. tranilast, 1,25dihydroxyvitamin D, erythropoietin or glitazones,whereas others are single-study reports or descriptivestudies without functional links to renal fibrosis(Table 2).

Conclusions

In the past years, many promising targets for thetreatment of renal fibrosis have been validated invarious animal models, and even more new targetshave been identified. For several of the targetsreviewed, substances/drugs have already been devel-oped, are being tested, or are already being therapeu-tically employed in patients with non-renal indications.Renal fibrosis, in contrast, remains a largely unchartedterritory in clinical trials. The reasons for this arecertainly multifactorial and may include long studydurations if hard endpoints, i.e. loss of GFR, are to beaimed for and, in particular, the lack of non-invasivemarkers or diagnostic tools to assess kidney scarring,and thus, monitor therapy. However, the industry hasnoted the enormous potential market, given thepossibility of developing antifibrotic therapy thatmight be of benefit in many different types of organfibrosis. Furthermore, there is hope that with a largeconsortia search for biomarkers and advancing ultra-sound, or through MR-based or molecular-imagingtechniques, even monitoring of the disease process maybecome feasible in the near future.

Acknowledgements. We apologize to all authors whose importantwork we could not cite due to space limitations. This work wassupported by grants from the Deutsche Forschungsgemeinschaft(DFG) OS 196/1-1 (T.O.) and SFB 542, project C7 (T.O., J.F.).

Conflict of interest statement. None declared.

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Received for publication: 7.3.07Accepted in revised form: 25.5.07


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