Abstract 65: Soluble Angiotensin Converting Enzyme 2 as an Additional Source of Blood Pressure Regulation within the Kidney

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Angiotensin Converting Enzyme 2 (ACE2) is a transmembrane carboxypeptidase that degrades angiotensin II (AngII) to Ang(1-7). This membrane-bound enzyme can be cleaved by metalloproteinases such as ADAM17, releasing the catalytically active ectodomain to generate soluble ACE2. The objective of this study is to determine if soluble ACE2, acting locally in the kidney, could modulate the blood pressure (BP) response to AngII infusion.

In order to isolate the actions of ACE2 in the kidney from systemic tissues, we utilized kidney cross-transplantation. We studied male (129/SvEv x C57BL/6)F1 ACE2 knockout (KO) and wild-type (WT) mice. Kidney transplants were performed to generate 4 experimental groups: 1) WT, 2) kidney ACE2KO, 3) systemic ACE2KO, and 4) total ACE2KO. Mean arterial BPs (MAP) were measured with radiotelemetry at baseline and during a 2-week infusion of AngII (1ug/kg/min). Enzymatic activity was determined using an ACE2-specific quenched fluorescent substrate assay.

Total ACE2KO mice had an enhanced hypertensive response to AngII compared to WT mice (152±6 vs.144±7 mmHg; p=0.03), consistent with our previous findings of enhanced susceptibility to AngII hypertension in mice globally deficient in ACE2. The presence of ACE2 in either the kidney or systemic tissues restored MAPs to levels similar to the WT group (kidney ACE2KO 140±7mmHg, systemic ACE2 KO 140±5 mmHg, p<0.01 vs. total KO). Serum ACE2 activity levels were decreased in systemic KO mice (40±35 RFU/ul/hr) but unaffected in kidney KO mice, compared to WT (153±25 vs. 126±26 RFU/ul/hr, respectively). However, despite genetic deletion from all kidney cells, kidney ACE2KO mice had similar urinary ACE2 activity compared to systemic ACE2KO (76±32 and 108±52 RFU/ul/hr, p=NS). Urinary ACE2 activity in WT mice was highest, 217±36 RFU/ul/hr, compared to total KO which was undetectable (p<0.001).

Our studies demonstrate that restoration of ACE2 in either the kidney or systemic tissues is sufficient to abrogate the exaggerated hypertensive response to chronic AngII infusion. Soluble ACE2 delivered to the kidney may be an additional source of ACE2 to act within the kidney since the cells produce no ACE2 locally in kidney KO mice. Our studies highlight a possible role of soluble ACE2 in BP regulation.

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