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A New Look at Platelet-Derived Growth Factor in Renal Disease

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A New Look at Platelet-Derived Growth Factor in Renal Disease BRIEF REVIEW www.jasn.org A New Look at Platelet-Derived Growth Factor 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 receptor chains (PDGFR-␣ and -␤), plays important roles in wound healing, 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 cell proliferation 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 deletion 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 ligand 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 mitogen and chemoattractant chain is encoded by the c-sis gene. 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 tyrosine renal disease has accumulated. These data PDGF-A and -B bind to various extracel- kinase activity and is autophosphory- have been reviewed previously,4 and this lular matrix proteins 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, endothelin, thrombin, lipopro- teins, lysophosphatidylcholine, phos- pholipids, and CpG nucleotides.4,28–30 Many mitogens 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 hepatocyte growth factor 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 phospholipase C, ras activates various proto-oncogenes and ation and migration. In general, GTPase activating protein, phosphati- immediate early response genes, 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 Janus kinase/signal transducers and downstream functions.21 on DNA synthesis.41 In contrast, activators of transcription 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. Autophosphorylation 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; protein kinase 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 fibroblasts 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).
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