A15268 Genetic deletion of AT1a Receptor selectively in the proximal tubule of the kidney attenuates renal ischemia-reperfusion injury and angiotensin II-induced hypertension in mice

Abstract

Objectives: To test the hypothesis that genetic deletion of angiotensin II (ANG II) AT1a receptors selectively in the proximal tubule of the kidney attenuates renal ischemia-reperfusion injury and ANG II-induced hypertension in mice. Methods: Proximal tubule-specific AT1a receptor-knockout mice (PT-AT1a-KO) were generated using the standard Cre/LoxP recombination approach. Adult male C57BL/6J (WT), global AT1a-KO, and PT-AT1a-KO mice were subjected to sham surgery or 45 min bilateral renal ischemia, followed by reperfusion for 24 h or 7 days (n = 8–12 per group). ANG II-dependent hypertension was induced by infusing ANG II at 1.5 mg/kg/day, i.p., for 2 weeks. Systolic blood pressure (SBP), renal function, glomerular, tubuointerstital, and perivascular injury were determined and compared, respectively. Results: Basal systolic blood pressure was 22 ± 5 mmHg lower in global AT1a-KO or 11 ± 3 mmHg lower in PT-AT1a-KO mice (p < 0.05 vs. WT). WT mice developed significant glomerular, cortical tubulointerstitial and perivascular injury 24 h or 7 days after renal ischemia-reperfusion was induced (p < 0.01). Ischemia and reperfusion renal injury was not prevented in global AT1a-KO mice (n.s. vs. WT), but it was significantly attenuated in PT-AT1a-KO mice 24 h or 7 days after renal ischemia-reperfusion was induced (p < 0.05 vs. WT or AT1a-KO). WT mice developed severe ANG II-induced hypertension, as expected, but it was significantly attenuated in PT-AT1a-KO mice (p < 0.01 vs. WT). Conclusion: AT1a receptors in the proximal tubule of the kidney play a key role in the pathogenesis of renal ischemia-reperfusion injury and ANG II-dependent Hypertension (supported by 2R01DK067299 and 2R01DK102429 to Zhuo, and by National Natural Science Foundation of China #81360290 and Guangxi Natural Science Foundation #2014GXNSFAA118195 to Zhang).