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::Pdgfcfl/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.