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A New Look at -Derived in Renal Disease

Ju¨rgen Floege,* Frank Eitner,* and Charles E. Alpers† *Department of Nephrology and Clinical Immunology, Rheinisch Westfa¨ lische Technische Hochschule University Hospital Aachen, Aachen, Germany; and †Department of Pathology, University of Washington, Seattle, Washington

ABSTRACT The PDGF system, comprising four isoforms (PDGF-A, -B, -C, and -D) and two identified specific PDGF-CC activating chains (PDGFR-␣ and -␤), plays important roles in , athero- protease, whereas PDGF-DD is activated sclerosis, fibrosis, and malignancy. Components of the system are expressed by urokinase-type plasminogen activa- constitutively or inducibly in most renal cells. They regulate a multitude of patho- tor.3 Excess free CUB domains might act physiologic events, ranging from and migration to extracellular as competitive antagonists for the full- matrix accumulation, production of pro- and anti-inflammatory mediators, tissue length growth factors by interacting with permeability, and regulation of hemodynamics. Genetic of PDGF-B or their specific proteases. PDGFR-␤ results in an absent glomerular mesangium, whereas PDGF-C and PDGF receptors (PDGFR) are dimers PDGFR-␣ contribute to the formation of the renal cortical interstitium. Almost all composed of ␣ and/or ␤ chains. Whereas experimental and human renal diseases are characterized by altered expression of PDGF-A binds to the ␣ chain only, components of the PDGF system. Infusion or systemic overexpression of PDGF-B PDGF-B is a for all receptor types or -D induces prominent mesangioproliferative changes and renal fibrosis. Intervention (Figure 1); however, at least in mesangial studies identified PDGF-C as a mediator of renal interstitial fibrosis and PDGF-B and cells (MC), PDGF-B exerts its biologic -D as key factors involved in mesangioproliferative disease and renal interstitial fibro- activity almost exclusively via the sis. These data establish PDGF as one of the best characterized growth factors in renal PDGFR-␤␤ or PDGFR-␣␤, despite ex- disease and the most potent stimulus of mesangial cell proliferation currently pression of both receptor chains by the identified. Accordingly, targeted intervention against the various PDGF isoforms cells.9,10 After proteolytic processing, the offers a promising novel therapeutic approach to renal disease. core domain of PDGF-CC seems to be largely a ligand for the PDGFR-␣, J Am Soc Nephrol 19: 12–23, 2008. doi: 10.1681/ASN.2007050532 whether present as the homodimer PDGFR-␣␣ or heterodimer PDGFR-␣␤, whereas PDGF-DD binds predomi- PDGF is a and chemoattractant chain is encoded by the c-sis . nantly to PDGFR-␤␤.3 for mesenchymal cells. It is important in PDGF-A occurs in two alternatively wound healing, atherosclerosis, organ fi- spliced versions. The longer 16-kD iso- brosis, and malignancy.1–3 During the past form is retained at the cell surface after PDGF SIGNALING 20 yr, considerable information on the role secretion, whereas the shorter isoform is of the various PDGF family members in released into the extracellular medium.5 The PDGF receptor possesses renal disease has accumulated. These data PDGF-A and -B bind to various extracel- activity and is autophosphory- have been reviewed previously,4 and this lular matrix and may become lated upon ligand binding.1 The receptor article primarily serves as an update with more diffusible after cleavage of a particular attention given to the discovery COOH-terminal retention sequence.1 of PDGF-C and -D in 2000 and 2001, re- The two novel PDGF isoforms, Published online ahead of print. Publication date spectively, and to the delineation of their PDGF-C and -D, are released as 55- and available at www.jasn.org. 2,3 6–8 roles in renal pathophysiology. 49-kD homodimers, respectively. Correspondence: Dr. Ju¨rgen Floege, Department Both are produced as latent factors, and of Nephrology and Clinical Immunology, University extracellular cleavage of the complement Hospital Aachen, Pauwelsstrasse 30, D-52057 BIOCHEMISTRY OF PDGF AND Aachen, Germany. Phone: ϩ49-241-8089530; Fax: subcomponent C1r/C1s, Uegf, and ϩ PDGF RECEPTORS 49-241-8082446; E-mail: juergen.floege@rwth- Bmp1 (CUB) domains is required for re- aachen.de

PDGF-A and -B are secreted as homo- or ceptor binding and activation (Figure Copyright © 2008 by the American Society of heterodimers (Figure 1). The 14-kD B 1).3 Tissue plasminogen activator is one Nephrology

12 ISSN : 1046-6673/1901-12 J Am Soc Nephrol 19: 12–23, 2008 www.jasn.org BRIEF REVIEW

in many cells of mesenchymal ori- gin.10,22–27 PDGF synthesis is induced in cultured MC by various mediators, in- cluding PDGF itself, EGF, basic fibro- blast growth factor, TNF-␣, TGF-␤, AngII, , thrombin, lipopro- teins, lysophosphatidylcholine, phos- pholipids, and CpG nucleotides.4,28–30 Many in fact exert their mito- genic effect through the induction of PDGF.31,32 Negative regulators of PDGF synthesis have also been identified and include platelet factor-4 and NOV/ CCN3.33,34 In glomerular endothelial cells, hypoxia is another inducer of PDGF-B chain synthesis, whereas shear stress re- duces it.35,36 In proximal tubular cells, hy- Figure 1. Schematic outline of the PDGF and PDGF receptor system showing the perglycemia is a strong stimulus for ␣ ␤ differential binding of the various PDGF isoform combinations to the PDGFR- and - PDGF.37 In these cells, growth factors such chains. tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator; as and TGF-␤, CUB, complement subcomponent C1r/C1s, Uegf, and Bmp1 domain. which are ultrafiltered in the glomerulus, may also act as PDGF inducers.38 then interacts with several other cyto- whereas AngII triggers only cell hyper- Stimulation of MC with different plasmic proteins containing SH2 do- trophy.18 In the nucleus, PDGF signaling PDGF ligands results in cellular prolifer- mains, including , ras activates various proto-oncogenes and ation and migration. In general, GTPase activating , phosphati- immediate early response , includ- PDGF-AA exerts at best weak effects on dyl-inositol 3-kinase (PI3-K), members ing c-fos, JunB, c-myc, and egr-1,19,20 MC proliferation.39,40 In metanephric of the pp60src family of protein tyrosine that are effectors of the receptor tyrosine mesenchymal cells, PDGF-AA causes kinase, tyrosine phosphatase SHP-2 and kinase and responsible for particular modest cell migration but has no effect the /signal transducers and downstream functions.21 on DNA synthesis.41 In contrast, activators of pathway.1,11 Homodimeric ␣␣ and ␤␤ receptor PDGF-BB stimulation of MC induces a Mutant mice expressing a PDGFR-␤ that complexes induce overlapping but dis- rapid mobilization of intracellular cal- can no longer activate PI3-K or phos- tinctly different effects on target cells, cium, decreases p27, and increases cyclin pholipase C-␥ exhibit attenuated PDGF- which might be explained by differential A and CDK2, resulting in pronounced dependent cellular functions but no re- interactions with various SH2 domain pro- cell proliferation.39,40,42,43 MC migration duction in survival.12 Second messengers teins. on different in response to PDGF-BB involves up- include inositol-1,4,5-triphosphate and tyrosine residues might explain the unique regulation of the cytoskeletal proteins diacylglycerol; intracellular calcium re- properties of the heterodimeric ␣␤ recep- moesin and radixin.44 MC proliferation lease; C-␣,-␤,-␧, and -␨; tor complex in comparison with ho- can also be induced by PDGF-CC and and prenylated, low molecular weight G modimeric receptors. Finally, PDGF -DD.9,25 In 3D culture, the MC respon- proteins.1,13,14 Mitogen-activated pro- signaling can also be modulated in the siveness to PDGF decreases markedly as tein kinase (MAPK) is a downstream tar- extracellular milieu by matrix mole- a result of PDGFR downregulation.40 get of PI3-K.15 Different MAPK, such as cules. Naturally occurring PDGF an- Mitogenic PDGF effects on other renal extracellular signal–regulated kinase, c- tagonists include secreted, truncated cell types are less consistent. PDGF does ␣ Jun N-terminal kinase, and p38, mediate receptor forms and 2-macroglobu- not affect proliferation in glomerular en- different effector functions in MC, such lin.1 The extracellular secreted protein, dothelial cells.45 Tubular epithelial cells as proliferation and TGF-␤ or chemo- acidic and rich in cysteine binds exhibit variable responses,46,47 and papil- kine synthesis in response to PDGF.16 In- PDGF-AB and -BB and thereby favors lary renal and to a lesser ex- hibition of extracellular signal–regulated PDGF-AA bioactivity.3 tent cortical fibroblasts respond with mi- kinase in vivo indeed ameliorated mesan- togenesis.48 gioproliferative nephritis.17 PDGF-BB PDGF also induce extracellular ma- and angiotensin II (AngII) differ in their STUDIES IN RENAL CELLS IN VITRO trix synthesis in MC, parietal epithelial potency and duration of activation of the cells, and, to a lesser degree, tubular MAPK cascade, which may explain why In general, PDGF are major autocrine or epithelial cells.49–53 They may affect PDGF-BB is a potent mitogen for MC, paracrine mitogens and survival factors this by acting upstream of and/or in con-

J Am Soc Nephrol 19: 12–23, 2008 PDGF and Renal Disease 13 BRIEF REVIEW www.jasn.org

Figure 2. Immunohistochemical localization of PDGF-D and its receptor PDGFR-␤ and of PDGF-C and its principle receptor PDGFR-␣ in human (A through D), mouse (E through H), and rat (I through K) glomeruli. Constitutive expression of PDGF-D is localized to podocytes in humans and MC in mice and is not detected in rat glomeruli. VSMC in all of these species express PDGF-D (E and I). PDGFR-␤ is expressed by MC and interstitial cells in all of these species. Expression of PDGFR-␤ by parietal epithelial cells is best seen in the human (B). PDGF-C is constitutively expressed in mouse MC and by microvascular endothelial cells in all three species. Although not visualized in this preparation, expression of PDGF-C by parietal epithelial cells has been reported. PDGFR-␣ is not normally detectable in human or mouse glomeruli but is expressed by interstitial cells. Studies of PDGFR-␣ expression in normal adult rat glomeruli are not available. cert with other such as TGF- tight and gap junctions in tubular cells PDGF-B chain is expressed by the differ- ␤.52,54,55 In contrast to TGF-␤, PDGF and MC, respectively.69,70 These latter ef- entiating of early-stage glo- exhibits little effect on matrix degrada- fects may also contribute to the increased merular vesicles (comma and S stage), tion.56,57 tissue permeability that is a characteristic but in later stages of glomerular develop- PDGF-BB stimulation of MC leads to of several kidney diseases. ment, the expression of PDGF-B chain is an increased expression of numerous limited to MC.72 PDGF-D expression has mediators of disease and inflammation, been identified in the epithelial cells of including TGF-␤1, CCL-2, CXC3CL1, NORMAL DISTRIBUTION IN comma- and S-shaped vesicles and in the plasminogen activator inhibitor-1, IL-6, EMBRYONIC AND ADULT visceral epithelial cells of later stage glo- endothelin-1, inducible nitric oxide syn- RODENT AND HUMAN KIDNEY meruli in developing human kidneys.73 thase, and YB-1.4,16,58–61 Through effects The localization of PDGF-A and -B on MC contraction and prostanoid pro- Early in metanephric kidney develop- and PDGFR-␣ and -␤ in postnatal hu- duction, PDGF also contributes to the ment, PDGFR-␣ and -␤ are expressed in man and rodent kidneys has been well regulation of glomerular hemodynam- the undifferentiated blastema, vascular established (Table 1). PDGFR-␣ is ics. Infusion of PDGF into isolated mi- structures (PDGFR-␤ only), and inter- widely expressed by renal interstitial cells croperfused glomeruli increases intra- stitium.71,72 mRNA encoding PDGFR-␣ and to some degree by MC.71 Constitu- glomerular pressure and vascular is present in some mesangial structures tive PDGFR-␣ expression by smooth resistance and decreases flow rate.62–64 in early glomeruli but is largely lost as muscle cells of the renal arterial vascula- Finally, PDGF affects very-low-con- glomeruli mature.72 During the transi- ture has been identified but is not uni- ϩ ductance Ca2 -permeable channels,65–67 tion from S-phase vesicles to identifiable form among these cells. PDGFR-␤ is ex- which regulate intracellular calcium and glomeruli, PDGFR-␤ is expressed uni- pressed postnatally by MC, glomerular thereby prevent in MC,68 as formly by cells differentiating into MC.72 parietal epithelial cells, and interstitial well as the permeability of intercellular In developing metanephric kidney, cells.74

14 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 12–23, 2008 www.jasn.org BRIEF REVIEW

Table 1. Expression of PDGF and PDGFR in normal adult kidney of various speciesa Parameter PDGF-A PDGF-B PDGF-C PDGF-D PDGFR-␣ PDGFR-␤ Glomerulus ϩ h141 ϩ h141 endothelial cells ϪϪϩm78 ϪϪϪ MC ϪϪϩ/Ϫ h142 ϩ/Ϫ m, r, h26,73,78 ϩ m, h71,143 ϩ m, h74,78 podocytes ϩ h75 ϪϪ ϩh73 ϪϪ parietal epithelial ϪϪϩ/Ϫ h77 ϪϪϩh74 cells Arteries smooth muscle cells ϩ m, h75,76,78 ϩ m78 ϩ m, r, h25,78,142 ϩ m, h73,78 ϪϪ endothelial cells ϩ h75 Ϫϩ/Ϫ m, h77,78 ϪϪϪ Tubules proximal tubules ϪϪ Ϫ Ϫ Ϫ Ϫ distal tubules ϩ m, h75,76 Ϫϩ/Ϫ h77 ϪϪϪ collecting ducts ϩ h75 Ϫϩr, h25,77 ϪϪϪ Interstitium ϩ h141 ϩ h141 interstitial cells ϪϪ ϩm, h71,76,78 ϩ m, h74,76,78 aϪ, not expressed; ϩ/Ϫ, inconsistent, species-specific, and/or controversial results; ϩ expressed; h, human; m, mouse; r, rat.

PDGF-A chain is normally ex- INSIGHT INTO RENAL arterial formation and func- pressed by mature podocytes and epi- DEVELOPMENT OBTAINED FROM tion.81–83 An almost identical renal phe- thelial cells of the distal nephron, in- GENETICALLY ALTERED MICE notype results from genetic ablation of cluding collecting ductal cells and PDGF-B in endothelial cells only,84 in urothelium.75 In the mouse, PDGF-A Genetically altered mice can provide im- PDGFR-␤–deficient mice,85 or when an chain also seems to be expressed by portant clues to the developmental role antagonistic anti–PDGFR-␤ mAb was cells of the loop of Henle.76 Although of individual proteins and can provide administered to neonatal mice, where low levels of PDGF-B chain expression clues to pathogenetic processes during outer cortical glomeruli still form after by MC in normal mature glomeruli renal disease in adult animals. PDGF- birth.86 Finally, when the matrix reten- may be present, it has been difficult to AϪ/Ϫ mice usually die on embryonic day tion motif within the PDGF-B molecule detect constitutive expression by these 10. Postnatally, surviving mice develop was deleted in mice, delayed formation cells using immunohistochemistry. emphysema but no renal abnormal- of the mesangium was again noted and Ϫ Ϫ Localization of the more newly rec- ities.79 PDGF-C / mice have been re- resulted in proteinuria and glomerulo- ognized PDGF isoforms has been ham- ported to die in the perinatal period and sclerosis.87 pered by the limited availability of reli- exhibit a complete cleft of the secondary Whereas PDGF-D null mice have able reagents. Important differences in palate.6 Mice with combined homozy- not been described yet, its overexpres- patterns of expression in mouse, ro- gous deficiency for PDGF-A and -C sion using a metallothionein promoter dent, and human kidneys have been re- among other defects lack elements of the resulted in no gross pathologic renal vealed (Figure 2, Table 1). PDGF-C has renal cortical interstitium and largely changes on embryonic day 15, but no been localized to arterial smooth mus- seem to mirror the phenotype of mice live transgenics were born (W. LaRo- cle cells and collecting duct epithelial deficient for PDGFR-␣.80 These observa- chelle, PhD, and M.J. Jeffers, PhD, cells in the rat. In humans, PDGF-C has tions point to potential roles of PDGF-A Curagen Corp., Branford, CT, personal been localized to parietal epithelial and -C and/or PDGFR-␣ in mediating re- communication, February 27, 2007). cells in the glomerulus, tubular cells nal interstitial disease, a notion that was re- When we specifically overexpressed from all parts of the nephron distal to cently confirmed by us (see Intervention PDGF-D in podocytes of mice, intra- the proximal tubules, and arterial en- Studies). glomerular pathology ranging from dothelial cells.25,77 In normal human Mice deficient for PDGF-B also die mesangioproliferative lesions to cres- adult kidneys, PDGF-D expression perinatally. The most notable abnormal- centic glomerulonephritis evolved.88 persists in podocytes and is constitu- ity is an absence of normal glomerular Collectively, these observations tively expressed by vascular smooth tuft formation as a result of a complete point to central and nonredundant muscle cells (VSMC).73 Constitutive lack of MC migration into the glomeru- roles of PDGF-B and -D and PDGFR-␤ expression of PDGF-D in the rat is lim- lar stalk, whereas glomerular endothelial in the development of the glomerular ited to VSMC only.26 In the mouse, cells, the basement membrane, and mesangium. The effects of PDGF-B PDGF-D is constitutively expressed in podocytes are largely preserved. Most and, by implication, PDGF-D and glomeruli but by MC and not podo- PDGF-B mutant embryos also develop PDGFR-␤ interactions that allow de- cytes in contrast to humans.78 fatal hemorrhages as a result of disturbed velopment of a mesangium are recapit-

J Am Soc Nephrol 19: 12–23, 2008 PDGF and Renal Disease 15 BRIEF REVIEW www.jasn.org ulated in mesangial regeneration after dent injury models, including mesan- as transplant glomerulopathy and again at mesangiolytic injury and in mesangio- gioproliferative anti–Thy 1.1 glomeru- sites of interstitial fibrosis.77 An upregula- proliferative responses to injury in ma- lonephritis, AngII-induced renal tion of PDGFR-␣ has been shown in ture rats (see Intervention Studies). damage, nephrotoxic nephritis, puro- VSMC and in tubulointerstitial cells in the With respect to therapeutic interven- mycin-induced FSGS, diabetic nephrop- course of different renal diseases.78,92 tions in renal patients, additional data athy, renal transplantation, ischemia/ Numerous publications have re- are of major importance: Transgenic reperfusion, murine lupus nephritis, and ported an overexpression of PDGF-B high-level overexpression of a soluble murine IgA nephropathy. Studies examin- in the course of renal diseases. Upregu- PDGF-B and -D antagonist (soluble ing the PDGF expression in human renal lation of PDGF-B has been reported in PDGFR-␤) in the during late em- tissues have focused on a similar spectrum MC, VSMC, tubular cells, interstitial bryogenesis and throughout postnatal of renal diseases (Table 2). cells, and, in rare instances, podocytes life in mice was not associated with any PDGF-A was overexpressed within in animal models and human renal dis- phenotype.89 This suggests that, in MC in models of mesangioproliferative eases (Table 2).90,93–97 The renal ex- contrast to embryogenesis, PDGF-B glomerulonephritis and within endo- pression of PDGF-D is comparably less and -D are not required during normal thelial and smooth muscle cells during well characterized, but an upregulation adult life. human vascular transplant rejec- has been detected in experimental mesan- tion.90,91 In animal models, PDGF-C gioproliferative glomerulonephritis and was upregulated in MC and podocytes in interstitial cells in the course of renal fi- EXPRESSION OF PDGF AND upon cellular injury and/or activation and brosis.26,78 Renal PDGFR-␤ overexpres- PDGFR IN RENAL DISEASE within the interstitium at sites of renal fi- sion has been detected in MC but also in brosis.25 In human renal biopsies, PDGF-C parietal epithelial cells, endothelial cells, Upregulated PDGF expression has overexpression was prominent in podo- tubular epithelial cells, and interstitial been observed in a large number of ro- cytes of membranous nephropathy as well cells.74,98–102

Table 2. Regulation of PDGF and PDGFR in renal diseasea Parameter PDGF-A PDGF-B PDGF-C PDGF-D PDGFR-␣ PDGFR-␤ Animal models glomerulusb ϩ144 ϩ94,98,144–155 ϩ90 ϩ98,146,151 endothelial cells MC ϩ90 ϩ90,94,95,146,152,153 ϩ25 ϩ26 ϩ90,146 podocytes ϩ93,146 ϩ25 ϩ/Ϫ93,146 parietal epithelial cells ϩ152,154 ϩ154 circulating leukocytes, ϩ95,152 arteriesb ϩ155 smooth muscle cells ϩ/Ϫ25 endothelial cells tubulesb ϩ78,96,99,156 ϩ97 ϩ97 interstitiumb ϩ99,157 ϩ78 ϩ78,99,156 interstitial cells ϩ158 ϩ78,99 ϩ25 ϩ78 ϩ78 ϩ78,156 ϩ25

Human renal diseases glomerulusb ϩ159 ϩ100,153,159–164 ϩ77 ϩ92,141 ϩ100,101,141,160,162,164,165 endothelial cells ϩ/Ϫ77 MC ϩ/Ϫ77 ϩ/Ϫ92 podocytes ϩ77 parietal epithelial cells arteriesb ϩ161 ϩ141 smooth muscle cells ϩ92 ϩ91 ϩ92 ϩ165 endothelial cells ϩ92 tubulesb ϩ166 ϩ73 interstitiumb ϩ78,164 ϩ77 ϩ78 ϩ92,141 ϩ78,141,159,165 interstitial cells ϩ78,164 ϩ77 ϩ78 ϩ92 ϩ78,164,165 macrophages ϩ91 aExpression in comparison with normal kidney: ϩ/Ϫ, limited to a few models/diseases or controversial results; ϩ, upregulation. Empty boxes denote lack of data or no change in expression from normal (see Table 1). bCell type not specified.

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OVEREXPRESSION OR hyperglycemic GK rats also resulted in -D in inducing mesangioproliferative PHARMACOLOGIC acute, transient MC proliferation and ac- changes as well as tubulointerstitial fi- ADMINISTRATION tivation.107 The induction of mesangio- brosis in the case of PDGF-B. proliferative changes was reproduced in Various studies have investigated the re- healthy mice and rats by hepatic trans- nal consequences of infusing or overex- fection with viral constructs encoding INTERVENTION STUDIES pressing the different PDGF isoforms in PDGF-B, resulting in elevated circulat- vivo. Infusion of even very high dosages ing levels of this isoform.104 Finally, glo- Little is known on the effects of PDGF-A of PDGF-AA (5 mg/kg) into healthy rats merular overexpression of PDGF-B also inhibition in vivo (Table 3). PDGF-A failed to induce renal pathology.103 Sim- drove bone marrow–derived cells to- chain antisense oligonucleotides im- ilarly, adenoviral transfection of mouse ward a mesangial-like phenotype in proved arterial and renal damage in liver with a construct encoding PDGF-C vivo.108 At very high dosages (5 mg/kg), stroke-prone spontaneously hyperten- and causing elevated circulating levels of PDGF-BB infusion into rats induced sive rats.109 Antagonism of PDGF-C us- this isoform did not induce renal abnor- dosage-dependent renal tubulointersti- ing a neutralizing antiserum reduced the malities.104 A novel biologic role of tial cell proliferation, myofibroblast extent of renal tubulointerstitial fibrosis PDGF-C, which has yet to be explored in formation, and fibrosis, which were re- after unilateral ureter ligation.110 These the kidney, is a very potent induction of versible after PDGF-BB infusion was ab- studies complement other studies in .105 rogated.103 which cardiac overexpression of Infusion of recombinant PDGF-BB Mice with high circulating levels of PDGF-C induced myocardial fibrosis.111 into healthy rats led to a selective increase PDGF-D after adenoviral transfection Various interventions that reduce of glomerular MC proliferation.106 PDGF- of the liver developed a severe mesan- MC proliferation in vivo, such as admin- induced MC proliferation and mesangial gioproliferative glomerulopathy, char- istration of , C-type natriuretic matrix accumulation were markedly aug- acterized by enlarged glomeruli and a , or antisense oligonucleotides mented when the MC had suffered a minor striking increase in glomerular cellu- against Egr-1, may act indirectly through (subclinical) injury before the PDGF infu- larity.104 Collectively, these data dem- inhibition of autostimulatory effects of sion.106 Administration of PDGF-BB to onstrate potent roles of PDGF-B and endogenously produced PDGF. Each of

Table 3. Effects of PDGF antagonism in models of renal diseasea Model Intervention Effects Reference Spontaneously hypertensive rats PDGF-A antisense oligonucleotides 2 renal damage 109 Murine unilateral ureteral obstruction Neutralizing anti–PDGF-C antiserum 2 tubulointerstitial fibrosis and leukocyte influx 110 Rat acute antithymocyte serum GN Neutralizing anti–PDGF-AB IgG 2 MC proliferation and matrix accumulation 116 Rat acute anti–Thy 1.1 GN Transfection of cDNA encoding the 2 MC proliferation and matrix accumulation 118 extracellular domain of PDGFR-␤ fused with IgG-Fc Rat acute anti–Thy 1.1 GN Anti–PDGFR-␤ IgG 2 MC proliferation and matrix accumulation 119 Rat acute anti–Thy 1.1 GN B-specific oligonucleotide aptamer 2 MC proliferation and matrix accumulation 117 Rat chronic anti–Thy 1.1 GN B-specific oligonucleotide aptamer 2 proteinuria, 1 renal function, 122 2 glomerulosclerosis and tubulointerstitial fibrosis Rat acute anti–Thy 1.1 GN Neutralizing anti–PDGF-D IgG 2 MC proliferation and matrix accumulation 26 Rat chronic anti–Thy 1.1 GN Neutralizing anti–PDGF-D IgG Ϯ proteinuria, 1 renal function, 123,124 2 glomerulosclerosis and tubulointerstitial fibrosis, 2 EMT Rat acute anti–Thy 1.1 GN Trapidil 2 MC proliferation and matrix accumulation 126 Rat acute anti–Thy 1.1 GN 2 MC proliferation and matrix accumulation 131,132 Rabbit nephrotoxic nephritis Trapidil Trend toward worse clinical data and renal 127 histology Murine streptozotocin-induced Imatinib 2 albuminuria, glomerular and tubulointerstitial 133 diabetes damage Murine lupus Imatinib 1 survival, 2 proteinuria, 2 glomerular and 134 tubulointerstitial damage Rat unilateral ureter obstruction AG 1295 2 tubulointerstitial fibrosis 136 Rat ischemia/reperfusion injury Trapidil, Ki6896 1 serum creatinine, 1 mortality rate, 97 2 proliferation of tubular epithelial cells aEMT, epithelial-to-mesenchymal transition; GN, glomerulonephritis.

J Am Soc Nephrol 19: 12–23, 2008 PDGF and Renal Disease 17 BRIEF REVIEW www.jasn.org these interventions also led to reduced have been evaluated in renal disease (Ta- has shown a good safety profile, whereas glomerular expression of PDGF-B ble 3). Some caution is necessary when in some patients with tumors, fluid re- chain.112–114 Similarly, aminoguanidine interpreting these studies, because many tention and ascites has been noted.139 reduced glomerular PDGF-B overex- of the kinase blockers exhibit only rela- pression and matrix accumulation in tive specificity for the PDGF receptor, streptozotocin-induced rodent diabe- and some, such as the c- kinase inhib- tes.115 itor imatinib (STI 571), were developed CONCLUSIONS A number of specific interventions primarily to inhibit other and aimed at neutralizing PDGF-B or -D or only reduce PDGFR-␣ and -␤ signaling From the wealth of data discussed, it is blocking the PDGF-␤ receptor have been as a “side effect.” Ki6896, like trapidil, obvious that PDGF is one of the best- shown to reduce MC proliferation and worsened rat renal ischemia/reperfusion characterized growth factor systems in matrix accumulation in rat anti–Thy 1.1 injury.97 In contrast, in all other injury renal disease. Altered expression of mesangioproliferative glomerulonephri- models tested, blockade of the PDGFR PDGF and/or its receptors is involved in tis (Table 3),26,116–119 whereas glomeru- was beneficial. Thus, most renal diseases and is an essential lar endothelial cell proliferation was not imatinib reduced mesangioproliferative component of mesangial and interstitial affected.120 PDGF-B antagonism in this changes in experimental glomerulone- proliferation and responses to injury. model did not affect the TGF-␤ system, phritis131,132; mildly ameliorated both re- Specific anti-PDGF interventions can suggesting that PDGF-B acts down- nal functional and structural parameters prevent important long-term sequelae in stream or independent of TGF-␤ and in diabetic apolipoprotein E knockout experimental models of renal disease. An may thus be a specific target to amelio- mice133; improved survival, renal func- obvious first human disease to test anti- rate both increased cellularity and matrix tion, and histology in murine lupus134; PDGF therapy is mesangioproliferative production.121 More important, tran- and prevented chronic allograft ne- glomerulonephritis, in particular IgA ne- sient PDGF-B or -D antagonism during phropathy after rat kidney transplanta- phropathy. Specific anti-PDGF com- the mesangioproliferative phase of pro- tion.135 Finally, another PDGF tyrosine pounds have been developed and tested gressive anti–Thy 1.1 glomerulonephri- kinase inhibitor, AG 1295, mildly de- in humans, including CDP860, a hu- tis prevented the subsequent develop- layed the development of interstitial fi- manized, PEGylated di-FabЈ that blocks ment of renal failure and glomerular as brosis in rats with unilateral ureteral ob- the PDGFR-␤, and CR002, a fully human well as tubulointerstitial scarring.122,123 struction136; however, at least in the case mAb to PDGF-D.139,140 Clearly, the time Beneficial effects of anti–PDGF-D treat- of imatinib, it is not always clear whether is ready for clinical trials of PDGF inter- ment were observed even when treat- the benefit observed related to inhibition vention. Imatinib, already approved for ment started after the acute mesangio- of the PDGFR tyrosine kinase or to inhi- human use as an antineoplastic agent, is a proliferative phase, suggesting that bition of the c-abl kinase, which also candidate therapeutic agent for this pur- PDGF-D antagonism also has a role in contributes to renal interstitial fibro- pose, but later generation tyrosine kinase retarding tubulointerstitial fibrosis.124 A sis.137 In addition, significant adverse ef- inhibitors are being tested for potentially role for PDGF-D in fibrotic disease is fects of imatinib on the myocardium better safety profiles. also suggested by the finding of cardiac have been related to inhibition of the c- Which research areas merit further fibrosis after heart-specific overexpres- abl kinase rather than the PDGFR ty- studies in this field? Effects of anti-PDGF sion.111 rosine kinase.138 therapy in other renal diseases, in partic- Trapidil, a nonspecific PDGF antago- Taken together, these data provide ular diabetic nephropathy and lupus ne- nist, markedly reduced PDGF-BB–in- strong evidence that inhibition of phritis, have not been well characterized duced proliferation of MC in vitro125 and PDGF-B and -D can be an effective ap- so far. Another field that has received lit- in vivo126; however, in rabbit accelerated proach to proliferative glomerulone- tle attention is the regulation of PDGF nephrotoxic nephritis and in rats with phritis and that both can also directly or bioactivity in renal disease. We have renal ischemia/reperfusion injury, clini- indirectly affect the progression of renal characterized a PDGF-regulated down- cal and histologic data worsened in tra- tubulointerstitial damage. Recent evi- stream antagonist, NOV/CCN3,34 and pidil-treated animals.97,127 Other drugs dence also suggests a beneficial effect of others may exist and be useful targets for that are used in patients with renal dis- PDGF-C antagonism in the latter pro- pharmacologic intervention. Uncharted ease, including calcium channel block- cess.110 At least two studies suggested territory also relates to the proteolytic ac- ers, lovastatin, and ramipril, also inter- that PDGF inhibition should be avoided tivation of the novel PDGF-C and -D iso- fere with PDGF signaling, but it is in instances of ischemia-reperfusion in- forms in renal disease as well as the role unknown whether the beneficial effect of jury of renal tubules.97 Although the po- of matrix binding of PDGF in the kidney. these drugs may be partly due to PDGF tential benefits of PDGF blockade in hu- Finally, novel activities such as the angio- inhibition.128–130 man renal disease is not yet known, it is genic properties of PDGF-CC may merit A number of low molecular weight noteworthy that specific inhibition of exploitation in models of thrombotic PDGF blockers PDGFR-␤ in normal volunteers so far microangiopathy.

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