Abstract 225: Loss of Either Renal or Systemic ACE2 contributes to the Hypertensive Response to Chronic Angiotensin II
Angiotensin Converting Enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin II (AngII). ACE2 is broadly expressed in cardiovascular tissues, with highest expression in the kidney. We have previously shown that mice with targeted deletion of the Ace2 gene have an exaggerated response to AngII-induced hypertension (HTN) associated with elevated renal AngII levels. Based on these findings, we now hypothesize that ACE2 in the kidney decreases AngII levels and is therefore responsible for its anti-hypertensive effects. To test this, we utilized renal cross-transplantation to eliminate ACE2 specifically from the kidney or all other tissues. We studied male ACE2 knockout (KO) mice and wild-type (WT) littermates on (C57BL/6 x 129/SvEv)F1 background. Kidney transplants were performed to generate four experimental groups: 1) wild-type, 2) renal ACE2 KO, 3) systemic ACE2 KO, and 4) global ACE2 KO. All kidney function was provided entirely by the single transplanted kidney. After baseline measurements, mice were infused with AngII (1000ng/kg/min) chronically for two weeks while mean arterial blood pressures (MAP) were measured with radiotelemetry. There were no significant differences in baseline MAPs among groups. Similar to our prior study, the response to AngII infusion was exaggerated in mice with global ACE2 deficiency compared to WT control mice (152±6 vs.144±7 mmHg; p=0.03, n=10). However, the presence of ACE2 in either the kidney or systemic tissues restored MAPs to levels similar to that of the WT group (renal ACE2 KO 140±7mmHg, p<0.01 vs. global ACE2 KO; systemic ACE2 KO 140±5 mmHg, p<0.01 vs. global KO). This effect was equivalent between the renal KO and systemic KO groups. Global ACE2 deficiency leads to an exaggerated hypertensive response to chronic AngII administration. Thus, restoration of ACE2 in either the kidney or in systemic tissues is sufficient to abrogate this enhanced hypertensive response. Our data suggest equivalent effects of both renal and extra-renal ACE2 in hypertension.
- © 2012 by American Heart Association, Inc.