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

Significance Statement We investigated the role of the profibrotic PDGF in the development and progression of FSGS in a murine model resembling human FSGS. Injured podocytes expressed PDGF-B, inducing parietal epithelial cell activation, proliferation, and a profibrotic switch–driving FSGS. Therapeutic inhibition of PDGF-B significantly reduced proteinuria and FSGS, suggesting that inhibition of the PDGF signaling pathway might be a potential novel treatment for patients with FSGS. Background FSGS is the final common pathway to nephron loss in most forms of severe or progressive glomerular injury. Although podocyte injury initiates FSGS, parietal epithelial cells (PECs) are the main effectors. Because PDGF takes part in fibrotic processes, we hypothesized that the ligand PDGF-B and its receptor PDGFR- β participate in the origin and progression of FSGS. Methods We challenged Thy1.1 transgenic mice, which express Thy1.1 in the podocytes, with anti-Thy1.1 antibody to study the progression of FSGS. We investigated the role of PDGF in FSGS using challenged Thy1.1 mice, 5/6 nephrectomized mice, Col4−/− (Alport) mice, patient kidney biopsies, and primary murine PECs, and challenged Thy1.1 mice treated with neutralizing anti–PDGF-B antibody therapy. Results The unchallenged Thy1.1 mice developed only mild spontaneous FSGS, whereas challenged mice developed progressive FSGS accompanied by a decline in kidney function. PEC activation, proliferation, and profibrotic phenotypic switch drove the FSGS. During disease, PDGF-B was upregulated in podocytes, whereas PDGFR- β was upregulated in PECs from both mice and patients with FSGS. Short- and long-term treatment with PDGF-B neutralizing antibody improved kidney function and reduced FSGS, PEC proliferation, and profibrotic activation. In vitro , stimulation of primary murine PECs with PDGF-B recapitulated in vivo findings with PEC activation and proliferation, which was inhibited by PDGF-B antibody or imatinib. Conclusion PDGF-B–PDGFR- β molecular crosstalk between podocytes and PECs drives glomerulosclerosis and the progression of FSGS.