Antagonism of PDGF-D by Human Antibody CR002 Prevents Renal Scarring in Experimental Glomerulonephritis

Ostendorf, Tammo; Rong, Song; Boor, Peter; Wiedemann, Stefanie; Kunter, Uta; Haubold, Ulrike; Roeyen, Claudia R.C. van; Eitner, Frank; Kawachi, Hiroshi; Starling, Gary C.; Alvarez, Enríque; Smithson, Glennda; Floege, Jürgen

doi:10.1681/asn.2005070683

Cited by 100 publications

(104 citation statements)

References 31 publications

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“…All PDGFs (A-D) have been shown to be up-regulated in conjunction with renal fibroses. Evidence for a role of PDGF-A and PDGF-C remains circumstantial, but PDGF-D has been shown to play a role in experimental mesangioproliferative glomerulonephritis in rats by use of a PDGF-D-specific neutralizing antibody (Ostendorf et al 2006). The source(s) of PDGF-B during mesangioproliferative pathology is not entirely clear.…”

Section: Renal Fibrosismentioning

confidence: 99%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

2,071

1,898

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-␣ signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-␤ signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974;Ross et al. 1974;Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983;Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.PDGF-A was characterized by cDNA cloning ). This resolved a paradoxical lack of correlation between secretion of PDGF-like growth factors from tumor cell lines and their expression of c-sis; it turned out that most such cell lines express PDGF-A and secrete PDGF-AA homodimers ). Together with the demonstration that PDGF-BB homodimers are produced by SSV-transformed or PDGF-Bexpressing cells, these results showed that the PDGF...

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Section: Renal Fibrosismentioning

confidence: 99%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

2,071

1,898

View full text Add to dashboard Cite

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“…121 More important, transient PDGF-B or -D antagonism during the mesangioproliferative phase of progressive anti-Thy 1.1 glomerulonephritis prevented the subsequent development of renal failure and glomerular as well as tubulointerstitial scarring. 122,123 Beneficial effects of anti-PDGF-D treatment were observed even when treatment started after the acute mesangioproliferative phase, suggesting that PDGF-D antagonism also has a role in retarding tubulointerstitial fibrosis. 124 A role for PDGF-D in fibrotic disease is also suggested by the finding of cardiac fibrosis after heart-specific overexpression.…”

Section: Intervention Studiesmentioning

confidence: 99%

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

Floege

Eitner

Alpers

2008

Journal of the American Society of Nephrology

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286

252

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“…On day 60, the percentage of glomeruli that exhibited focal or global glomerulosclerosis was determined as described previously (13). Tubulointerstitial injury, defined as inflammatory cell infiltrates, tubular dilation, and/or atrophy or interstitial fibrosis on day 60, was graded on a scale of 0 to 4 as described previously (14). The total number of glomerular cross-sections was determined by counting within a longitudinal renal 4-m section all glomeruli per 20 consecutive 1-mm 2 areas of the renal cortex.…”

Section: Evaluation Of Histologic Sectionsmentioning

confidence: 99%

“…Normally, antiThy1.1 nephritis in rats follows a self-limited course, and spontaneous restitution of the glomerular architecture can be observed within approximately 4 wk. For enhancement of the relevance of the model for progressive renal disease in humans, the model in this study was aggravated and transformed into a course of progressive renal failure by previous uninephrectomy of the rats (7,8).…”

mentioning

confidence: 99%

Mesenchymal Stem Cells Prevent Progressive Experimental Renal Failure but Maldifferentiate into Glomerular Adipocytes

Kunter

Rong

Boor

et al. 2007

Journal of the American Society of Nephrology

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258

163

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Glomerulonephritis (GN) isM esenchymal stem cells (MSC) hold special promise for renal repair, because nephrons are largely of mesenchymal origin (1). The potential of MSC for renal repair has been shown in rodent models of acute renal failure (ARF), where the course of glycerol, cisplatin, or ischemia-reperfusion induced ARF was improved by MSC injection shortly after disease induction (2-5). In addition, we recently reported that injection of rat MSC into a renal artery can accelerate recovery from mesangiolytic damage and prevent transient ARF in rat anti-Thy1.1 glomerulonephritis (GN) (6). AntiThy1.1 nephritis is a model of acute mesangioproliferative glomerulonephritis and is characterized by initial mesangiolysis followed within a few days by glomerular repair via endothelial and mesangial cell proliferation and accumulation of mesangial matrix. We have also provided evidence that MSC likely exerted these effects in glomeruli by paracrine effects, such as the release of high amounts of vascular endothelial growth factor (VEGF) and TGF-␤1 rather than by differentiation into resident glomerular cell types or monocytes/macrophages (6).In this study, we investigated the long-term effects of MSC administration in early anti-Thy1.1 nephritis. Normally, antiThy1.1 nephritis in rats follows a self-limited course, and spontaneous restitution of the glomerular architecture can be observed within approximately 4 wk. For enhancement of the relevance of the model for progressive renal disease in humans, the model in this study was aggravated and transformed into a course of progressive renal failure by previous uninephrectomy of the rats (7,8). Materials and MethodsRats were housed under standard conditions in a light-, temperature-, and humidity-controlled environment with free access to tap water and standard rat diet. All animal protocols were approved by the local government authorities. Harvest and Culture of MSCInbred male Lewis rats that weighed 180 to 210 g (Harlan, Horst, Netherlands) served as bone marrow donors; MSC were prepared as described previously (6). Cells were seeded onto six-well plates (nine

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Antagonism of PDGF-D by Human Antibody CR002 Prevents Renal Scarring in Experimental Glomerulonephritis

Cited by 100 publications

References 31 publications

Role of platelet-derived growth factors in physiology and medicine

Role of platelet-derived growth factors in physiology and medicine

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

Mesenchymal Stem Cells Prevent Progressive Experimental Renal Failure but Maldifferentiate into Glomerular Adipocytes

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