Die Rolle von PDGF-D in der Nierenfibrose

About 8-16% of the world population suffers from chronic kidney disease. Chronic kidney diseases lead to development of kidney fibrosis, which enhances the loss of kidney function even more.Although chronic kidney diseases have a high morbidity and mortality the treatment options are still limited. Thus new therapeutic options are needed urgently.In this study the role of Platelet-derived Growth Factor D (PDGF-D) in kidney fibrosis was analyzed. PDGF-D is a specific ligand of the PDGF receptor β (PDGFR-β). This receptor regulates central mechanisms like proliferation, migration and cell survival as well as production of extracellular matrix. It is known that in glomeruli PDGFR-β activation on mesangial cells by PDGF-D mediates proliferation, but the role of PDGF-D in the interstitium, especially in fibrosis, was still unknown. This study confirms the expression of PDGF-D in mesenchymal kidney cells, including the mesangial cells, fibroblasts and vascular smooth muscle cells. In human and murine kidney fibrosis the expression of PDGF-D and its receptor PDGFR-β are both increased. This increase occurs in interstitial (myo-)fibroblasts as well as de novo in damaged tubuli. The functional role of PDGF-D was analyzed using PDGF-D knockout mice (Pdgfd-/-). These mice were viable and showed no obvious pathological phenotype in the kidney, neither in young nor in old ages. This indicates that PDGF-D is dispensable for normal development and physiology of the kidney. Comparing Pdgfd-/- mice with wildtype littermates Pdgfd-/- mice developed significantly less fibrosis in two different models of kidney fibrosis, the unilateral ureteral obstruction and the unilateral ischemia/reperfusion model. This was associate with decreased phosphorylation of PDGFR-β and its downstream kinase p38. Furthermore PDGF-D revealed to have an influence on extracellular matrix homeostasis through regulatory effects on the TIMP/MMP system. As a proof-of-principle systemic adenoviral PDGF-D overexpression in healthy wildtype mice lead to increased accumulation of extracellular matrix in the kidney interstitium. Summing up PDGF-D showed to be a pro-fibrotic mediator of interstitial fibrosis and therefore could be a therapeutic target for treatment of kidney fibrosis.