Abstract 010: Renal Proximal Tubule-derived Angiotensin Converting Enzyme 2 (ACE2) in Blood Pressure Regulation

Abstract

Angiotensin Converting Enzyme 2 (ACE2) is a carboxypeptidase that metabolizes angiotensin II (AngII) to Ang1-7, playing a critical role in blood pressure (BP) regulation. Previous studies from our lab demonstrated that loss of ACE2 resulted in enhanced susceptibility to AngII hypertension and this was associated with elevated renal AngII levels. ACE2 is highly expressed in kidney, particularly in proximal tubule epithelia, and kidney cross-transplant experiments performed by our group revealed a novel mechanism by which ACE2 may be functioning to regulate BP. However, the exact cellular sources and sites of action where ACE2 regulates BP remain unclear. The objective of this study is to assess proximal tubule-derived ACE2 in BP regulation by studying a new mouse model generated in our laboratory: proximal tubule-specific ACE2 knock-out mice (referred to as ACE2 PTKO mice). ACE2 PTKO mice were generated by crossing the Ace2 -flox/flox conditional mouse line with the phosphoenolpyruvate carboxykinase (PEPCK)-Cre mouse (V. Haase, Vanderbilt). ACE2 PTKO mice and their littermate control mice were inbred 129/SvEv, co-caged, and only males were studied. ACE2 PTKO mice exhibited reduced ACE2 mRNA and protein in renal cortex compared to controls ( Ace2 mRNA relative expression: 0.47 ± 0.1 vs. 1.08 ± 0.1, N=3 vs 3, P <0.05; relative ACE2 protein expression: 0.38 ± 0.04 vs. 1.15 ± 0.12, N=3 vs 3, P <0.01). Measured with radiotelemetry, there were no differences in BPs between ACE2 PTKO mice and control mice (119 ± 1 vs 117 ± 2 mmHg, N=16 vs 16, p=NS) at baseline. However, ACE2 PTKO mice exhibited an enhanced hypertensive response during the first week of AngII infusion compared to control mice (139.9 ± 4.8 vs 152.8 ± 3.7 mmHg at day 7, N=16 vs 16, P =0.038). Furthermore, the ACE2 KO kidneys accumulated significantly higher renal AngII than control kidneys, measured at day4 (897±104 vs 536±115 fmol/g, P <0.05). Our data demonstrate that proximal tubule-derived ACE2 plays a critical role in BP regulation during AngII infusion. The enhanced hypertensive response in ACE2KO mice is consistent with their intra-renal AngII levels, suggesting that that proximal tubule-derived ACE2 regulates BP via metabolizing AngII within the kidney.