Tubular cell-specific platelet-derived growth factor-B drives formation of fibrogenic niches in kidney fibrosis

Introduction Kidney fibrosis is the underlying pathological process of chronic kidney disease, a major global medical challenge. In most diseases, fibrosis-initiating injury affects epithelial cells. However, the fibrosis-executing cells are interstitial mesenchymal cells, particularly fibroblasts, expressing the platelet-derived growth factor (PDGF) receptor β (PDGFR-β). Here, we analyzed the cell-specific functional relevance of the PDGFR-β ligand, PDGF-B, in the cellular crosstalk in kidney fibrosis. Methods Following a transcriptome-wide gene expression analysis of PDGF-B in murine and human kidney tissues, we generated transgenic mouse lines with deletion of Pdgfb in major cellular sources of PDGF-B and analyzed kidney phenotypes and fibrogenesis in different kidney fibrosis models. Results Mice with Pdgfb deletion in kidney tubular epithelial cells showed smaller kidneys and slightly altered microstructure revealed by pathomics, without affecting the overall development or kidney function, even at high age (100 weeks). In three models with tubular injury of different etiologies (ureteral obstruction, ischemia/reperfusion and adenine-enriched diet), mice lacking Pdgfb in tubular cells had significantly and specifically reduced activation and proliferation of peritubular PDGFR-β + cells and fibrosis. Single-cell expression and cell-cell interaction analysis revealed a paracrine PDGF-B/PDGFR-β signaling axis between tubules and fibroblasts in mice and humans. Even a single PDGF-B-expressing injured tubular cell could drive fibrogenesis by induction of a surrounding peritubular interstitial profibrotic niche. Despite PDGF-B being expressed or stored in kidney mesenchymal cells or megakaryocytes and platelets, Pdgfb deletion in these cells had no effect on healthy or fibrotic kidney models. Conclusion Paracrine PDGF signaling represents a key molecular mechanism of cellular crosstalk mediating the transition of kidney tubular injury to interstitial fibrosis.