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 ⅚ nephrectomy (⅚ Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or ⅚ Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT1 receptor antagonist losartan, MLN plus losartan, or ANG-(1–7) for 4 wk. In ⅚ 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 ⅚ Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. ⅚ 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 ⅚ Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with ⅚ Nx alone, an effect reversed by losartan. Treatment of ⅚ 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 ⅚ Nx. Inhibition of ACE2 in ⅚ Nx mice increases albuminuria via an AT1 receptor-dependent mechanism, independent of BP. In contrast, ANG-(1–7) does not affect albuminuria after ⅚ Nx. We propose that endogenous ACE2 is renoprotective in CKD.
Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout
