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Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-β1 and collagen I and elevated renal Ang-(1–7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100 nmol L−1) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-β1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1 mg mL−1) or mTOR inhibitor rapamycin (10 μmol L−1). These protective effects of rhACE2 were eradicated by the Ang-(1–7)/Mas receptor antagonist A779 (1 μmol L−1). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1–7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders.Reduction of ACE2 and activation of mTOR signaling are observed in the kidneys of ApoE-deficient mice.Ang II infusion results in marked increases in renal TGF-β1 levels and tubulointerstitial fibrosis in ApoE-null mice.ACE2 has anti-fibrotic properties with normalization of Ang II-mediated mTOR/ERK activation and enhanced renal Ang-(1–7) levels.Treatment with rhACE2 and rapamycin prevent Ang II-induced superoxide generation and mTOR activation in mouse kidney fibroblasts.