title: Angiotensin-converting enzyme 2 ameliorates renal fibrosis by blocking the activation of mTOR/ERK signaling in apolipoprotein E-deficient mice.
abstract: 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 (1.5mg/kg) and/or human recombinant ACE2 (rhACE2; 2mg/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 (100nmolL(-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 (1mgmL(-1)) or mTOR inhibitor rapamycin (10μmolL(-1)). These protective effects of rhACE2 were eradicated by the Ang-(1-7)/Mas receptor antagonist A779 (1μmolL(-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.
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Lai-Jiang
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors.forename: Ying-Le
authors.initials: YL
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, Guangzhou 510080, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton T6G 2S2, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Department of Mental Health, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Ding-Liang
authors.initials: DL
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. Electronic address: jiuchangzhong@aliyun.com.
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy; D005355:Fibrosis; D007668:Kidney / Q000201:enzymology / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D010446:Peptide Fragments; D000803:Angiotensin I; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D020123:Sirolimus
keywords: Angiotensin-converting enzyme 2; Apolipoprotein E; Atherosclerosis; Renal fibrosis; mTOR