Renal Interstitial Platelet-Derived Growth Factor Receptor-β Cells Support Proximal Tubular Regeneration

Background The kidney is considered to be a structurally stable organ with limited baseline cellular turnover. Nevertheless, single cells must be constantly replaced to conserve the functional integrity of the organ. PDGF chain B (PDGF-BB) signaling through fibroblast PDGF receptor-beta (PDGFR beta) contributes to interstitial-epithelial cell communication and facilitates regenerative functions in several organs. However, the potential role of interstitial cells in renal tubular regeneration has not been examined. Methods In mice with fluorescent protein expression in renal tubular cells and PDGFR beta-positive interstitial cells, weablated single tubular cells by high laser exposure. We then used serial intravital multiphoton microscopy with subsequent three-dimensional reconstruction and ex vivo histology to evaluate the cellular and molecular processes involved in tubular regeneration. Results Single-tubular cell ablation caused the migration and division of dedifferentiated tubular epithelial cells that preceded tubular regeneration. Moreover, tubular cell ablation caused immediate calcium responses in adjacent PDGFR beta-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFR beta-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFR beta-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFR beta impeded PDGFR beta-positive cell migration to the tubular injury site and compromised the recovery of tubular function. Conclusions Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFR beta-mediated communication between the renal interstitium and the tubular system.