SP277CONSTITUTIVE ACTIVATION OF PDGFR-β IN RENAL MESENCHYMAL CELLS DRIVES RENAL FIBROSIS

Introduction and Aims: Platelet-derived Growth Factor Receptor β (PDGFR-β), is involved in several human disease and drives organ fibrosis, yet only few studies suggested its involvement in renal fibrosis. PDGFR-β is upregulated in fibrosis and specifically expressed on the mesenchymal cells centrally involved in renal fibrosis, i.e. glomerular mesangial cells, interstitial fibroblasts and pericytes. Methods: Here we analyzed the role of activation of PDGFR-β specifically in renal mesenchymal cells using a transgenic FoxD1-driven activation of a constitutively active PDGFR-β mutant. Results: The mutant animals showed increased phosphorylation of PDGFR-β and primary mesangial cells and fibroblasts showed significantly increased proliferation in vitro and in vivo compared to control mice. In glomeruli, mutant mice developed glomerular mesangial hypercellularity and sclerosis. This was progressive, becoming diffuse and global with time and resulted in increasing glomerular volume. In the interstitium, mutant mice showed expansion of interstitial (myo)fibroblasts and interstitial fibrosis compared to control mice. This was not associated with a prominent inflammatory response or hypertension. The mutant mice developed renal anemia in the absence of prominent uremia as well as secondary tubular injury in later time-points. Compared to controls, mutant mice developed a more severe fibrosis after ischemia-reperfusion injury.