ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney

Abstract

Angiotensin‐converting enzyme 2 (ACE2) is highly expressed in the kidney and hydrolyzes angiotensin II (Ang II) to Ang(1–7). Since Ang II is a strong activator of oxidative stress, we reasoned that ACE2 could be involved in the regulation of renal oxidative stress by governing the levels of Ang II. We, therefore, assessed levels of oxidative stress in kidney cortex of ACE2 knockout and wild‐type littermate mice under baseline conditions. We found multiple markers of increased oxidative stress in ACE2KO mice. NADPH oxidase activity was increased in kidney cortex from ACE2KO mice as compared to WT (227 ± 24% vs.100 ± 19%, P < 0.001). However, kidney catalase and superoxide dismutase activities were not different between groups. Exogenous Ang II was degraded less efficiently by kidneys from ACE2KO mice than WT mice, and administration of an AT1R blocker (losartan 30 mg/kg/day) resulted in normalization of NADPH oxidase activity in the ACE2KO. These findings suggest that an AT1R‐dependent mechanism contributes to increased ROS observed in the ACE2KO. This study demonstrates that genetic deficiency of ACE2 activity in mice fosters oxidative stress in the kidney in the absence of overt hypertension and is associated with reduced kidney capacity to hydrolyze Ang II. ACE2KO mice serve as a novel in vivo model to examine the role of overactivity of NADPH oxidase in kidney function.

Renal oxidative stress and renal CD8+ T-cell infiltration in mercuric chloride-induced nephropathy in rats: role of angiotensin II

“…In a previous report, increased renal expression of Ang II in rats treated with HgCl 2 was noted . Increased levels of endogenous Ang II promote local tissue damage by several mechanisms, including oxidative stress (Wysocki et al 2014), mainly through activation of NADPH oxidase and increased formation of O À 2 (Toda et al 2007;Garrido & Griendling 2009;Harrison & Gongora 2009;Wysocki et al 2014). Since Losartan and Enalapril treatment diminished the high levels of renal O À 2 found in the present study, a role for induced NADPH oxidase mediated by Ang II could be expected.…”

“…Since Losartan and Enalapril treatment diminished the high levels of renal O À 2 found in the present study, a role for induced NADPH oxidase mediated by Ang II could be expected. Indeed, blocking of AT1 receptor by Losartan reduced NADPH oxidase activity in several experimental models (Toda et al 2007;Wysocki et al 2014). In conjunction with any enhanced O À 2 production caused by Ang II, HgCl 2 could concurrently be decreasing local superoxide dismutase (SOD) activity (Jo et al 2004), leading to overall increases in renal O À 2 content.…”

“…Because Ang II can be chemotactic for T-cells (SilvaFilho et al, 2011) and this hormone can mediate oxidative stress (Toda et al 2007;Garrido & Griendling 2009;Harrison & Gongora 2009;Wysocki et al 2014), it could be expected that Ang II would modulate those parameters during HgCl 2 -induced nephropathy. Ang II acts through two receptor subtypes, AT1 and AT2 receptors.…”

Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis

“…Wysocki et al. (30) demonstrated that the genetic ablation of ACE2 in mice was associated with increased kidney ROS owing to elevated levels of NADPH oxidase activity. Other studies demonstrated that both apoptosis and oxidative stress, two processes that are associated with I/R and are influenced by Ang II, were exacerbated by the loss of the Ace2 gene (31,32) and that repetitive episodes of hypoxia/reoxygenation that are associated with the transient cessation of breathing during sleep in OSA resemble I/R injury (33).…”

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

“…Besides, ACE2 deficient mice have shown exacerbated NOX activity in the kidney and Ang-(1-7) treatment has presented inhibitory effects on ROS formation via the attenuation of NOX function [122].…”