Renal Interstitial Platelet-Derived Growth Factor Receptor- 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- (PDGFR) 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-positive interstitial cells, we ablated single tubular cells by high laser exposure. We then used serial intravital multiphoton microscopy with subsequent three-dimensional reconstruction and 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-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFR-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFR-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFR impeded PDGFR-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-mediated communication between the renal interstitium and the tubular system.