The role of ACE2 and its product, angiotensin-(1-7), in a model of early chronic kidney disease

Abstract

Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II to angiotensin- (1-7) (Ang-(1-7)). The role of ACE2 and Ang-(1-7) in the progression of chronic kidney disease (CKD) is unclear. We studied the effects of ACE2 inhibition and Ang-(1-7) in the 5/6 nephrectomy (5/6 Nx) mouse model of CKD and sought to generate kidney-specific ACE2 transgenic mice. We hypothesized that pharmacological inhibition of ACE2 would accelerate kidney injury in 5/6 Nx mice whereas administration of Ang-(1-7) might be renoprotective. Four weeks after 5/6 Nx, kidney cortex ACE2 protein expression and enzymatic activity were decreased, compared to Sham-operated mice. In 5/6 Nx mice, ACE2 inhibition significantly increased urine albumin excretion, an effect reversed by Ang II AT1 receptor antagonism. In contrast, Ang-(1-7) did not affect CKD progression. Finally, using a plasmid vector containing the human ACE2 gene linked to the nephrin promoter, transgenic mice were generated that selectively overexpress human ACE2 in the glomerular podocyte. These data suggest that kidney ACE2 is down-regulated in the 5/6 Nx mouse and that further inhibition of ACE2 increases albuminuria via an AT1 receptor-dependent mechanism. The generation of ACE2 transgenic mice will allow for further delineation of the physiological role of ACE2 in the kidney.