The protective role of ACE2 in hypertension Academic Article uri icon

abstract

  • ACE2 is a recently identified homologue of ACE that has been shown to cleave Ang I to Ang 1-9, which in turn is cleaved by ACE to Ang 1-7. ACE2 also cleaves Ang II to form Ang 1-7. Since Ang 1-7 is a potent vasodepressor peptide, its action could counterbalance the vasopressor effect of Ang II. ACE2 could thus be a counter-regulator of ACE in maintaining vascular tone. To study the hypothesis that ACE2 plays a role in hypertension, the rat ACE2 gene was cloned and placed by radiation hybrid mapping on rat chromosome X, adjacent to a hypertension related QTL (SS-X) previously detected in the Sabra rat model of salt-sensitive hypertension. ACE2 expression was measured by Northern analysis and found it to be the most expressed (+4) in the rat kidneys and to a lesser extent (+1) in the rat heart, aorta, lung and retina, with no detectable expression in the brain, adrenals, muscle or fat tissue. Gene expression was determined in whole kidneys of Sabra hypertension prone (SBH/y) and resistant (SBN/y) rata by Northern analysis and Western blotting. While on regular chow, mRNA and protein levels were consistently 20-40% higher in SBN/y than in SBH/y; when salt-loaded, ACE2 levels were unchanged in normotensive SBN/y but decreased in hypertensive SBH/y, rendering the differences between the strains even larger (50-70%). These experimental data obtained in the Sabra rat model of hypertension lend support to a novel mechanism for hypertension according to which: (1) ACE2 regulates vascular tone by counter-balancing ACE activity; (2) in the presence of reduced ACE2 expression, Ang 1-7 vasodepressor peptide levels are diminished in SBH/y, allowing Ang II activity to predominate and leading to increased vascular tone and consequently hypertension during salt-loading; and (3) that vice versa, increased ACE2 expression in SBN/y leads to increase levels of Ang 1-7 and decreased levels of Ang II, thus preventing the rise in BP from occurring during salt-loading and exerting a vascular “protective” effect which maintains normotension. A novel mechanism is thus being revealed whereby ACE2 acts as a protective protein that prevents the development of hypertension. (See Figure)

publication date

  • January 5, 2003