Epithelial PDGF-C Contributes to Crescentic Glomerulonephritis and FSGS in Part via Activation of Parietal Epithelial Cells

Background: Activated parietal epithelial cells (PECs) and podocytes are key effector cells in the development of crescentic glomerulonephritis and focal segmental glomerulosclerosis (FSGS). Platelet-derived growth factor (PDGF)-C has been found to be important for tubulointerstitial fibrosis development, but its relevance for crescentic glomerulonephritis and FSGS was previously unknown. Methods: To address this, expression analyses for both PDGF-C and its receptor PDGFRα were carried out in mouse and human kidney tissues. To further elucidate a functional role of PDGF-C, the murine nephrotoxic nephritis model of crescentic glomerulonephritis was induced in a) Pdgfc -deficient mice, b) mice treated with a neutralizing PDGF-C antibody, and c) Pax8-cre::Pdgfc fl / fl mice with conditional Pdgfc deletion in kidney epithelial cells. We also subjected the collapsing FSGS model of the anti-Thy1.1 transgenic mouse to pharmacological PDGF-C inhibition. The studies were supplemented by PEC in vitro analyses. Results: Our data showed that PDGF-C was upregulated in PECs and expressed de novo in podocytes under disease conditions. It promoted the proliferation and activation of primary as well as conditionally immortalized PECs in vitro . In both the genetic and pharmacological PDGF-C intervention studies in murine crescentic glomerulonephritis and FSGS, significant improvements in glomerular crescent formation, glomerular sclerosis, renal inflammation and kidney function parameters were observed upon PDGF-C deficiency or antagonism. Mechanistically, transcription factor FOXM1 was identified as a mediator of disease-related PDGF-C expression in PECs. Conclusions: Our studies identified epithelial PDGF-C as a contributor to disease progression in crescentic glomerulonephritis and FSGS, acting in part through the activation of parietal epithelial cells.