Abstract
BackgroundThe renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys.MethodsThe 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro-inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys.ResultsDownregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1-7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang II-infused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels.ConclusionsACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE-mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases.
Highlights
The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases
Jin et al J Transl Med (2015) 13:255 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the apolipopro‐ tein E (ApoE)-mutant mice associ‐ ated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling
angiotensin-converting enzyme 2 (ACE2) deficiency resulted in modest elevations in Systolic blood pressure (SBP) levels and increased renal Ang angiotensin II (II) levels in both the single ACE2-mutant and ApoE/ACE2 double-mutant mice with accompanying decreases in renal Ang-(1-7) levels and the Ang-(1-7)/Ang II ratio (Table 2; Fig. 1)
Summary
The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. Atherosclerosis is considered one of the major risk factors for renal injury and the progression of chronic kidney diseases (CKD) to end-stage renal diseases (ESRD), which is costly and important clinical event with substantial morbidity [1,2,3,4]. Patients with CKD have a substantially increased risk for atherosclerotic cardiovascular death and total mortality and loss of renal parenchyma accelerates atherosclerosis in animal models [3, 5, 6], indicating the interplay between atherosclerosis and kidney injury. The pathophysiologic mechanisms underlying the accelerated progression of renal dysfunction in atherosclerosis status and the interactions between the RAS and nephrin signaling in atherosclerotic kidney injury remain to be fully clarified
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