title: Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Downregulation 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.
  
  
  CONCLUSIONS
  ACE2 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.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. hyjin603@163.com.|Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Department of Mental Health, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. hyjin603@163.com.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. cljalex@163.com.|Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. cljalex@163.com.
authors.forename: Lai-Jiang
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. zhangbochuan1227@163.com.|Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. zhangbochuan1227@163.com.
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. jerenatvxq@126.com.
authors.forename: Ying-Le
authors.initials: YL
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. 88497280@qq.com.
authors.forename: Bei
authors.initials: B
authors.lastname: Song
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. xuranxxzj@163.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, T6G 2S2, Canada. gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. gaopingjin@sibs.ac.cn.|Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. gaopingjin@sibs.ac.cn.
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. zhudingliang@sibs.ac.cn.|Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Department of Mental Health, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. zhudingliang@sibs.ac.cn.|Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. zhudingliang@sibs.ac.cn.
authors.forename: Ding-Liang
authors.initials: DL
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China. jiuchangzhong@aliyun.com.|Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Department of Mental Health, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. jiuchangzhong@aliyun.com.|Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. jiuchangzhong@aliyun.com.
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008565:Membrane Proteins; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D013481:Superoxides; D000804:Angiotensin II; D000803:Angiotensin I; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)