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 non-diabetic 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 non-diabetic floxed controls, db/db mice and PRRKO-db/db mice were studied at 16, 20, 26 and 30 weeks of age. PRR KO mice were only studied at 30 weeks of age. To induce PRR deletion, PRR KO and PRRKO-db/db mice were treated with 2 mg/ml doxycycline for 12 days at 8-10 weeks of age. Compared to controls, db/db mice and PRRKO-db/db mice had higher body weights throughout the study and elevated blood glucose levels at weeks 16 and 20. Compared to controls and db/db mice, PRRKO-db/db mice had higher urine volume, water intake and urinary albumin excretion. At 30 weeks, kidney histology showed minimal tubular or glomerular injury among all 4 groups. PRR KO mice had elevated expression of tubular injury markers compared to the other 3 groups. Plasma sPRR levels were almost two-fold 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 which is exacerbated by type 2 diabetes.