PPARγ promotes urothelial remodeling during urinary tract obstruction

Urinary tract obstruction (UTO) is a common cause of kidney injury that can result in chronic kidney disease and end-stage renal disease. Heterogeneity in the extent of obstructive renal damage in humans with UTO implies the existence of unknown mechanisms that protect against or accelerate kidney injury. Prior studies show that congenital and acquired UTO initiate a conserved, protective program of renal urothelium remodeling that culminates in expansion of uroplakin (UPK)⁺ cells to promote renal structural integrity. However, the cellular and molecular mechanisms that regulate UPK expression in the renal urothelium are unknown. Peroxisome proliferator-activated receptor γ (PPARγ) drives urothelial differentiation and UPK expression in other tissues but has not been investigated in the renal urothelium. Here we demonstrate that activation of PPARγ in UPK⁺ cells is critical for UTO-induced renal urothelium remodeling. Conditional deletion of Pparg perturbs UPK expression and accelerates parenchymal thinning during UTO, while conditional activation of PPARγ increases UPK expression and results in parenchymal preservation. This study underscores the significance of renal urothelium during UTO and shows that UTO-induced renal urothelial remodeling is achieved through activation of PPARγ. These findings form the foundation for future studies that will determine the therapeutic utility of PPARγ agonists during congenital and acquired UTO.