Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats


Corresponding author I. Hamming: Department of Pathology and Laboratory Medicine, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Email: i.hamming@path.umcg.nl


Angiotensin-converting enzyme (ACE) 2 is thought to counterbalance ACE by breakdown of angiotensin (Ang) II and formation of Ang(1–7). Both enzymes are highly expressed in the kidney, but reports on their regulation differ. To enhance our understanding of the regulation of renal ACE and ACE2, we investigated renal ACE and ACE2 expression during conditions of physiological (low-sodium diet) and pharmacological changes (ACE inhibition) in activity of the renin–angiotensin–aldosterone system (RAAS). Healthy rats were treated with vehicle or lisinopril with either a control or a low-sodium diet, and renal ACE2, ACE and plasma angiotensins were studied. During vehicle treatment, low sodium reduced renal ACE mRNA and activity without affecting ACE2 mRNA or activity and plasma Ang(1–7) and Ang II balance. Lisinopril significantly reduced renal ACE activity without affecting renal ACE2 activity. During ACE inhibition, low sodium reduced both ACE and ACE2 mRNA without affecting ACE2 activity or further reducing ACE activity. Measurements of renal neprilysin activity revealed no significant differences between any of the treatment groups. Plasma Ang(1–7) and Ang II balance is positively shifted towards the beneficial vasopeptide Ang(1–7) by the ACE inhibitor lisinopril, especially during a low sodium intake. In conclusion, modulation of the RAAS, by low sodium intake or ACE inhibition, does not affect renal ACE2 despite major variations in renal ACE. Thus, ACE and ACE2 are differentially regulated by low sodium and ACE inhibition. Therefore, we propose that the beneficial effects of ACE inhibitors are predominantly mediated by modulation of ACE and not ACE2. Whether this also applies to renal disease conditions should be investigated in future studies.