Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the 5/6 nephrectomy (5/6 Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or 5/6 Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the [AT.sub.1] receptor antagonist losartan, MLN plus losartan, or ANG(1-7) for 4 wk. In 5/6 Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In 5/6 Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. 5/6 Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in 5/6 Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with 5/6 Nx alone, an effect reversed by losartan. Treatment of 5/6 Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after 5/6 Nx. Inhibition of ACE2 in 5/6 Nx mice increases albuminuria via an [AT.sub.1] receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after 5/6 Nx. We propose that endogenous ACE2 is renoprotective in CKD. renin-angiotensin system; nephrectomy; albuminuria doi: 10.1152/ajprenal.00426.2009.