SAT-109 NEW INSIGHTS INTO THE NOVEL ROLES OF ANGIOTENSIN AT1A RECEPTORS IN THE PROXIMAL TUBULES OF THE KIDNEY IN ANGIOTENSIN II-INDUCED HYPERTENSION AND KIDNEY INJURY

Abstract

It is well-recognized that the renin-angiotensin system plays powerful endocrine, paracrine, and intracellular roles in the physiological regulation of blood pressure, cardiovascular and kidney function, as well as in the development of hypertension and kidney diseases. The present study tested the hypothesis that genetic deletion of AT1a receptors selectively in the proximal tubules of the kidney attenuates angiotensin II (ANG II)-induced hypertension and renal ischemia-reperfusion injury using global and proximal tubule-specific AT1a receptor knockout mouse models. Global and proximal tubule-specific AT1a receptor-knockout mice (PT-AT1a-KO) were bred, or generated in this laboratory using the standard Cre/LoxP recombination approach. The hypothesis was tested in the following experimental protocols. Three groups (n=12 per group) of age- and body wt.-matched adult male C57BL/6J (WT), global AT1a-KO (Agtr1a-/-), and PT-AT1a-KO mice were first used to measure basal systolic, diastolic, and mean arterial blood pressure using the telemetry and tail-cuff techniques. Another two groups of WT, AT1a-KO, and PT-AT1a-KO mice (n=8-12 per group) were infused with saline (control) or a pressor dose of ANG II at 1.5 mg/kg/day, i.p., for 2 weeks. Additional three groups of WT, AT1a-KO and PT-AT1a-KO mice (n=8-12 per group) were treated with sham surgery (control) or 45 min bilateral renal ischemia, followed by reperfusion for 24 h or 7 days. Blood pressure and renal functional responses, and glomerular, tubuointerstitial, and perivascular injury were determined accordingly. Under basal conditions, systolic, diastolic and mean arterial blood pressure was 23 ± 3 mmHg lower in global AT1a-KO (p<0.01 vs. WT), and 12 ± 3 mmHg lower in PT-AT1a-KO mice (p<0.01 vs. WT). 24 h urine output and urinary sodium excretion were significantly higher in AT1a-KO and PT-AT1a-KO than in WT mice (p<0.01). Urine osmolality was significantly lower in AT1a-KO mice (p<0.01), but to a much less extent in PT-AT1a-KO mice (p<0.05). The kidney wt. to body wt. ratio was smaller in AT1a-KO mice (p<0.01), but was not different between WT and PT-AT1a-KO mice. In response to ANG II infusion, systolic, diastolic and mean arterial blood pressure were significantly increased by 45 ± 5 mmHg (p<0.01 vs. baseline) in WT mice, but only by 25 ± 3 mmHg in PT-AT1a-KO mice (p<0.01 vs. baseline). The ANG II-induced hypertension was completely prevented in global AT1a-KO mice (n.s. vs. baseline). In response to induction of renal ischemia-reperfusion injury, WT mice developed significant glomerular, cortical tubulointerstitial and perivascular injury 24 h or 7 days after renal ischemia-reperfusion was induced (p<0.01), as expected. However, both acute and chronic ischemia-reperfusion renal injury was not attenuated in global AT1a-KO mice (n.s. vs. WT). Surprisingly, however, acute and chronic ischemia-reperfusion renal injury was significantly attenuated in PT-AT1a-KO mice 24 h or 7 days after renal ischemia-reperfusion was induced (p<0.01 vs. WT or AT1a-KO). The results of the present study provide the direct evidence for an important role of ANG II and AT1a receptors in the proximal tubules of the kidney in maintaining physiological blood pressure homeostasis, and in the full development of ANG II-dependent Hypertension and renal ischemia-reperfusion injury in mice.