Untersuchungen zur Rolle des renalen, intrinsischen Platelet-Derived Growth Factor (PDGF)-C versus PDGF-C aus dem hämatopoetischen System für die Entstehung von Nierenfibrose sowie Untersuchungen zur Bedeutung des genetischen Hintergrundes für die pro-fibrotische Rolle dieses Wachstumsfaktors

摘要

Irrespective of their origin, nearly all chronic kidney diseases end up in tubulointerstitial fibrosis and finally in end-stage renal disease (= ESRD) with the necessity of kidney replacement therapy. Strategies for early recognition and treatment of patients with chronic kidney disease are therefore urgently required. In recent years it became evident that the Platelet-Derived Growth Factor (PDGF)-system has a major role in pro-fibrotic processes in the kidney. Especially the isoform PDGF-C obviously plays a key role in these processes, as has been shown in a study in 2008, where deficiency or antagonism of PDGF-C blocked the development of renal fibrosis in experimental murine fibrosis (unilateral ureteral obstruction, UUO). Moreover, it could be shown that a considerable amount of PDGF-C in this model derived from infiltrating, PDGF-C overexpressing macrophages. In particular with regard to potentially more targeted therapeutic approaches the central aim of the present work was therefore to identify the origin of the pro-fibrotic PDGF-C in the kidney. For this aim PDGF-C-deficient C57BL/6 mice and their wildtype littermates were subjected to myeloablative irradiation and subsequent bone marrow transplantation with bone marrow either from PDGF-C-deficient or wildtype-mice. After a recovery phase of four weeks renal fibrosis was induced by unilateral ureteral obstruction. As a result, most of the investigated fibrosis and inflammation parameters were not different between all experimental groups. Therefore, the answer to the question whether mainly renal intrinsic or circulating PDGF-C, expressed from directly bone marrow descending, PDGF-C-expressing macrophages drives renal fibrosis, could not be finally resolved. This was mainly due to some characteristic features of the experimental setting, which were identified in follow-up experiments in this work and showed that a) there was a significantly reduced general extent of fibrosis-induction in C57BL/6 mice compared to SV129 mice, b) there was a reduced renal fibrosis by irradiation/bone marrow transplantation per se and finally c) there were potential consequences of a chimerism with the “sex of the bone marrow” on fibrosis induction. However, tracking of PDGF-C-deficient cells by a ß-Gal reporter in combination with the results of immunohistochemistry stainings of the renal tissues for infiltrating macrophages led us to conclude that PDGF-C from mobilized, bone marrow-derived macrophages has no or only a minor role for the induction of fibrosis in the kidney. In contrast, PDGF-C from renal parenchymal cells and from resident monocytes/macrophages seems to be more important in this process.