Cell-Specific Role of Platelet-Derived Growth Factor Subunit B (PDGF-B) in Kidney Fibrosis

Background: Kidney fibrosis is a critical pathological process in progressive kidney diseases. Platelet-derived growth factor (PDGF) has been implicated in the development and progression of kidney fibrosis, yet the exact cellular origins remain unclear. Methods: Three transgenic mouse lines were generated with cell-specific Pdgfb deletion in platelets, fibroblasts or epithelial cells. Spontaneous phenotypes were analyzed in young and aged male and female animals. Kidney fibrosis was induced by unilateral ureteral obstruction, ischemia-reperfusion injury or 0.2% adenine diet. Kidney function was analyzed by blood and urine analysis and perfused kidneys were investigated with histological, immunohistochemical, and immunofluorescence stainings, molecular biology and protein biochemical analyses. Results: Mice with megakaryocyte- and platelet-specific Pdgfb deletion exhibited neither a spontaneous kidney phenotype nor altered fibrosis development in disease models, challenging the conventional understanding of fibrosis as wound healing, in which “platelet-derived” growth factors play a major role. PDGF-B, and its receptor PDGFR-β, are expressed by mesenchymal cells in the kidneys, and some studies suggested potential autocrine effects. Deletion of Pdgfb in mesenchymal cells had no effects on normal development, aging or disease model progression, suggesting negligible effects of autocrine signaling in the kidney. In contrast, mice with Pdgfb deletion in kidney tubular epithelial cells exhibited smaller kidneys with reduced interstitium, particularly in the medulla, without compromising overall development or physiological kidney function, even at advanced ages. Furthermore, in three distinct models featuring tubular injury from various causes, mice lacking Pdgfb in tubular cells displayed significantly reduced fibrosis. The diminished paracrine PDGF-B/PDGFR-β signaling between tubules and peritubular fibroblasts led to decreased activation and proliferation of peritubular PDGFR-β+ cells, ultimately altering the profibrotic niche in the interstitium. Conclusion: Our findings unveil a PDGF-driven molecular mechanism of paracrine cellular crosstalk mediating the transition from tubular injury to interstitial fibrosis.