MO066: The Role of Platelet-Derived Growth Factor in Focal Segmental Glomerulosclerosis

Abstract BACKGROUND AND AIMS Focal segmental glomerulosclerosis (FSGS) describes a primary disease of podocytes (podocytopathy) and a secondary consequence of severe or progressive glomerular damage. No specific treatment options exist for FSGS, with many patients progressing to end-stage kidney disease. While podocyte injury is considered to initiate FSGS, parietal epithelial cells (PECs) were shown to be one of the main effector cells forming FSGS. Given the involvement of platelet-derived growth factor (PDGF) in fibrotic processes, we hypothesized that PDGF signaling is involved in the formation and progression of FSGS. METHOD We analyzed the role of PDGF in FSGS development and progression using a murine Thy1.1 trangenic FSGS model, patient kidney biopsies and primary murine PECs. In a second step, we therapeutically treated mice with FSGS with a neutralizing anti-PDGF-B antibody. RESULTS The podocyte-specific Thy1.1 transgenic mice 3 weeks after anti-Thy1.1 antibody injection showed reduced kidney function due to FSGS development. In this model, compared with control mice, PECs were progressively activated (63.3-fold increase in CD44 expression), showed a significantly increased proliferation (14-fold increase in Ki67 expression), followed by glomerular extracellular matrix deposition (2.6-fold increase in collagen 4) and FSGS development. Fluorescence in situ hybridization showed that mRNA of Pdgfb and Pdgfd was elevated in podocytes and Pdgfrb was upregulated in PECs during the time course of the disease. Similarly, in human FSGS biopsies, gene expression of both ligands, PDGFB and PDGFD, was elevated in podocytes and PDGFRB was increased in PECs compared with healthy glomeruli. Stimulation of primary mouse PECs with PDGF-B and PDGF-D in vitro led to significant activation (1.37- and 1.44-fold increase in CD44 expression, respectively), proliferation (1.46- and 1.36-fold increase, respectively), migration and extracellular matrix production (1.40-fold increase in fibronectin after PDGF-D stimulation) which could be inhibited by imatinib or a neutralizing PDGF-B antibody. In mice with FSGS, both a short- and long-term treatment with PDGF-B neutralizing antibody improved kidney function and reduced FSGS, PEC proliferation and profibrotic activation. CONCLUSION PDGFR-β and its ligands PDGF-B and PDGF-D were upregulated in experimental and clinical samples with FSGS in PECs and podocytes, respectively, and the inhibition of PDGF-B reduced PEC proliferation and FSGS development. This suggests paracrine cross-talk between injured podocytes and PECs, leading to PECs activation toward a profibrotic (pro-FSGS) phenotype and FSGS development. Thus, PDGF represents a novel molecular pathway in FSGS pathogenesis and potential target for therapy.