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TY - THES AU - Paffenholz, Pia Valerie TI - Untersuchungen zur Rolle von Platelet-Derived Growth Factor (PDGF)-C in einem Modell des akuten Nierenversagens, der renalen Ischämie, Reperfusion CY - Aachen PB - Publikationsserver der RWTH Aachen University M1 - RWTH-CONV-145291 SP - 125 S. : Ill., graph. Darst. PY - 2014 N1 - Aachen, Techn. Hochsch., Diss., 2014 AB - Inspite of a growing success in the investigation of causes and the development of acute kidney injury it remains an important medical and economic problem. Especially the high mortality rate after AKI could hardly be reduced within the last four decades. In our study of the potentially protective role of PDGF-C in the model of murine ischemia/reperfusion (IR) we compared its pathology between PDGF-C+/+- and PDGF-C-/-mice for a period of three weeks. All four PDGF-isoforms were – at the latest from day 5 onward – overexpressed in the kidney, PDGF-C instead had a twofold higher mRNA-expression during the complete period of observation which showed rather a moderate increase compared to control animals. At all three time points there was no differential mRNA-expression between PDGF-C+/+- and PDGF-C-/-mice of all PDGF-isoforms and PDGF-receptors. On day 1 after IR we could show, in comparison with sham-operated animals, a stronger tubular damage, more apoptosis, an upregulated renal infiltration by F4/80-positive and ER-HR3-positive macrophages as well as Ly6G-positive neutrophil granulocytes and an upregulated mRNA-expression of the proinflammatory mediators MCP-1, RANTES and CCR2 as well as the biomarkers NGal and KIM-1. We could not find any differences between the two genotypes. On day 5 we found a downregulation of F4/80-positive macrophages and T-lymphocytes as well as a reduced mRNA-expression of the chemokines MCP-1 in PDGF-C-/-mice. The other examined parameters, like tubular damage, ER-HR3-positive macrophages, Ly6G-positive neutrophil granulocytes, proinflammatory mediators, apoptosis, proliferation and the biomarkers NGal and KIM-1 showed no difference between PDGF-C+/+- and PDGF-C-/-mice, but were upregulated compared to sham animals. 21 days after IR we discovered significantly less tubulointerstitial fibrosis in PDGF-C-/-mice in comparison with wildtype mice. We observed reduced levels of collagen I and IV in immunohistochemistry, but no differences in the mRNA-expression of alpha-SMA and the fibrosis parameters collagen I, III, IV and fibronectin between both genotypes. PDGF-C-/-mice had a reduced infiltration by ER-HR3-positive macrophages as well as T-lymphocytes. Furthermore, there was also no difference in the renal infiltration by F4/80-positive macrophages, the expression of the proinflammatory cytokines MCP-1, RANTES and the chemokine receptor CCR2 as well as the biomarkers NGal and KIM-1. All analysed parameters were upregulated compared to sham-operated animals. In contrast to our original hypothesis we could not find a protective, but rather a proinflammatory influence of PDGF-C in the acute phase of renal IR on the days 1 and 5, which led to a significantly increased tubulointerstitial fibrosis in the late phase (day 21). Therefore we concluded that the inhibition of PDGF-C could be a useful treatment of acute and chronic kidney diseases. KW - Platelet-derived Growth Factor (SWD) LB - PUB:(DE-HGF)11 UR - https://publications.rwth-aachen.de/record/444980 ER -