Krt5⁺ urothelial cells are developmental and tissue repair progenitors in the kidney.

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5⁺) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)⁺ RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk⁺ RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk⁺ RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk⁺ RUCs derive from embryonic and neonatal Krt5⁺ RUCs, whereas Krt5⁺ RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5⁺ RUCs break their lineage restriction and robustly differentiate into Upk⁺ RUCs. Thus, Krt5⁺ RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk⁺ RUCs in a temporally restricted manner.

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