Renal tubular (pro)renin receptor deletion exacerbates kidney injury in db/db mice.

The (pro)renin receptor (PRR) is a multifunctional protein implicated in blood pressure regulation and kidney fibrosis. Previous studies report enhanced PRR expression in nondiabetic and diabetic kidney disease. In this study, we investigated whether deletion of renal tubular PRR attenuates kidney injury in type 2 diabetes. Floxed PRR mice were bred with mice expressing Pax8 rtTA and LC1 transgenes and db/db mice (B6.BKS) to obtain renal tubular PRR knockout (KO)-db/db mice. Male, age-matched nondiabetic floxed controls, db/db mice, and PRR KO-db/db mice were studied at 16, 20, 26, and 30 wk of age. PRR KO mice were only studied at 30 wk of age. To induce PRR deletion, PRR KO and PRR KO-db/db mice were treated with 2 mg/mL doxycycline for 12 days at 8-10 wk of age. Compared with controls, db/db mice and PRR KO-db/db mice had higher body weights throughout the study and elevated blood glucose levels at weeks 16 and 20. Compared with controls and db/db mice, PRR KO-db/db mice had higher urine volume, water intake, and urinary albumin excretion. At 30 wk, kidney histology showed minimal tubular or glomerular injury among all four groups. PRR KO mice had elevated expression of tubular injury markers compared with the other three groups. Plasma soluble PRR (sPRR) levels were almost twofold higher in diabetic mice relative to controls with no difference between db/db mice and PRR KO-db/db mice. Renal tubular deletion of PRR does not protect against kidney injury in type 2 diabetes; rather, the loss of PRR impairs baseline tubular function that is exacerbated by type 2 diabetes.NEW & NOTEWORTHY We investigated whether renal tubular deletion of the PRR would be protective in mice with type 2 diabetes. Longitudinal assessment to 30 wk of age demonstrated that diabetic mice with deletion of renal tubule PRR had higher albuminuria whereas gene expression of kidney injury markers was elevated in PRR KO mice at baseline compared with diabetic floxed controls and nondiabetic controls. Genetic deletion of PRR results in tubular cell dysfunction that is exacerbated by diabetes.