Renal Interstitial Platelet-Derived Growth Factor Receptor-<i>β</i> Cells Support Proximal Tubular Regeneration.

Abstract

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-<i>β</i> (PDGFR<i>β</i>) 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. In mice with fluorescent protein expression in renal tubular cells and PDGFR<i>β</i>-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 <i>ex vivo</i> histology to evaluate the cellular and molecular processes involved in tubular regeneration. 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<i>β</i>-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFR<i>β</i>-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFR<i>β</i>-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFR<i>β</i> impeded PDGFR<i>β</i>-positive cell migration to the tubular injury site and compromised the recovery of tubular function. Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFR<i>β</i>-mediated communication between the renal interstitium and the tubular system.