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

Area of Science:

• Urology
• Developmental Biology
• Nephrology

Background:

• Congenital urinary tract obstruction (UTO) is a primary cause of pediatric chronic kidney disease.
• Current treatments for UTO do not prevent end-stage renal disease, necessitating novel interventions.
• Understanding renal urothelial remodeling is crucial for developing therapies against obstructive nephropathy.

Purpose of the Study:

• To identify the cellular origin of uroplakin-positive (Upk+) renal urothelial cells (RUCs).
• To investigate the role of Krt5+ RUCs in urothelial plaque formation during development and in response to UTO.
• To determine if Krt5+ RUCs retain progenitor capacity in response to UTO.

Main Methods:

• Utilized fate mapping analysis to trace RUC origins during normal development and UTO.
• Examined the temporal restriction of progenitor capacity in Krt5+ RUCs.
• Assessed the differentiation potential of Krt5+ RUCs in response to experimental UTO.

Main Results:

• Adult Upk+ RUCs originate from embryonic and neonatal Krt5+ RUCs.
• Krt5+ RUCs lose their progenitor capacity and become lineage-restricted by postnatal day 14 under normal conditions.
• In response to UTO, Krt5+ RUCs labeled at postnatal day 14 regain differentiation capacity and generate Upk+ RUCs.

Conclusions:

• Krt5+ RUCs are the progenitors of Upk+ RUCs, crucial for forming the protective urothelial plaque.
• This progenitor capacity is temporally regulated, being active during development but re-activated by UTO.
• Identifying the source of Upk+ RUCs provides a potential therapeutic target for reversing obstructive nephropathy.