M.Sc Thesis

M.Sc StudentCohen-Segev Ravit
SubjectThe Involvement of ACE and ACE-2 in Renal and Cardiac
Dysfunction in Rats with Experimental Heart
DepartmentDepartment of Medicine
Supervisor PROF. Zaid A. Abassi


Background: The role of Angiotensin II (Ang II) in the pathogenesis of CHF has been well established. However, the involvement of Angiotensin 1-7 (Ang 1-7) and ACE2 in this phenomenon is largely unclear. This study examined (a) Expression of ACE and ACE2 in the renal and cardiac tissues of CHF rats, and (b) Acute and chronic renal and cardiac effects of Ang 1-7, AVE0991 (Ang 1-7 agonist), and A779 (Ang 1-7 antagonist) in these rats.

Methods: CHF was induced by surgical creation of aorto-caval fistula. ACE and ACE2 immunoreactivities were determined in the renal and cardiac tissues of CHF rats and their sham controls. In the acute protocol, the effects of incremental doses of Ang 1-7, AVE0991, or A779 on glomerular filtration (GFR), renal plasma flow (RPF), urinary flow (V), urinary sodium excretion (UNaV), and urinary excretion of cyclic GMP (UcGMP) were determined in these rats. In the chronic protocol, the effects of 4-week treatment with the above described compounds on kidney function and cardiac hypertrophy were evaluated in these animals.

Results: ACE and ACE2 immunoreactivities in the heart and kidney were ~2 fold higher in CHF rats. Acute infusion of either Ang 1-7 or AVE0991 at a high dose into CHF rats evoked significant increases in V, UNaV, GFR and RPF along enhanced UcGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative V and UNaV than their controls. Chronic administration of Ang 1-7 and AVE0991 exerted significant diuretic and natriuretic effects in CHF rats, but not in sham. Serum Cr and Aldo levels were significantly higher in vehicle-treated CHF rats. Treatment with Ang 1-7 and AVE0991 reduced these parameters. Noteworthy, chronic administration of Ang 1-7 to CHF rats caused reduction of cardiac hypertrophy.

Conclusions: This study demonstrates that ACE and ACE2 are activated in CHF. Upregulation of ACE2 and Ang 1-7 with their beneficial actions may compose a compensatory response in face of the deleterious classic RAAS to prevent worsened renal and cardiac dysfunctions.