Incomplete repair causes permanent defects in renal medullary structure and function after reversal of urinary obstruction

Urinary obstruction causes injury to the renal papilla and leads to defects in the ability to concentrate urine which predisposes to progressive kidney injury. However, the regenerative capacity of the papilla after reversal of obstruction is poorly understood. To address this, we developed a mouse model of reversible urinary obstruction which is characterized by extensive papillary injury, followed by a robust regeneration response and complete histological recovery over a 3-month period. However, these mice have a pronounced defect in urinary concentrating capacity. We now show that this is due to permanent changes in the composition, organization, and transcriptional signatures of epithelial, endothelial, and interstitial cell lineages in the papilla. There are persistent inflammatory responses that are also seen in patients with renal stone disease but are associated with cell-specific adaptive responses to the increasingly hypoxic environment of the papilla after reversal of obstruction. Taken together, our analysis of a new model of reversible urinary obstruction reveals that partial repair leads to permanent changes in the structure and function of all of the major cellular compartments in the papilla that include both shared and distinct responses to different types of renal papillary injury in humans and mice. Overall design: Papillae were dissected at two times points of injury (d28, d84 after R-UUO) and from healthy controls. We pooled 3-4 papilla per sample, and included 4 replicate samples (each with 3-4 papilae per sample) from healthy controls, 4 samples from D28, and 2 samples from D84 after RUUO