Renal tubular (pro)renin receptor deletion does not protect against kidney injury in db/db mice

Background: 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. Methods: 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. 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. To induce PRR deletion, PRRKO-db/db mice were treated with 2 mg/ml doxycycline for 12 days at 8-10 weeks of age. Only male mice were included in this study. Results: All mice survived until the end of the study (N=5-7 mice/group). Compared to controls, db/db mice and PRRKO-db/db mice had higher body weights despite similar food intake throughout the study (p<0.001 by one-way ANOVA). PRRKO-db/db mice had higher urine volume and water intake compared to controls and db/db mice (p <0.01 by ANOVA). Db/db mice had elevated non-fasting blood glucose levels (average: 472 mg/dl at 16 weeks, 292 mg/dl at 30 weeks) while PRR KO-db/db mice had modestly elevated blood glucose levels (average 255 mg/dl at 20 and 30 weeks) relative to controls (average: 150 mg/dl). Urinary albumin excretion was markedly elevated in PRRKO-db/db mice relative to db/db mice and controls throughout the study (950 ug/day vs db/db:145 ug/day, controls: 50 ug/day, p<0.001). At 30 weeks, kidney histology by PAS stain showed minimal tubular injury, glomerulosclerosis or interstitial inflammation among all 3 groups. Interestingly, podocin staining by immunofluorescence was reduced in db/db mice but not PRR-KO db/db mice. Compared to control mice, db/db mice had similar KIM-1, NGAL and collagen-1 mRNA expression in kidney cortex and inner medulla. PRR KO db/db mice had increased cortical KIM-1, NGAL and collagen-I expression compared to control and db/db mice (p<0.01 by ANOVA). 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. Urinary sPRR levels were undetectable in controls and mildly elevated in db/db mice (7.6 ± 0.7 pg/day) and PRR KO-db/db mice (47.6 ± 22.3 pg/ml). No differences in plasma prorenin/renin concentration was noted among the 3 groups while urinary prorenin/renin excretion was higher in PRRKO-db/db mice. Conclusion: Renal tubular deletion of PRR does not protect against kidney injury in type 2 diabetes. It is possible that loss of PRR impairs baseline tubular function which is exacerbated by type 2 diabetes. American Diabetes Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.