title: Role of angiotensin-converting enzyme (ACE and ACE2) imbalance on tourniquet-induced remote kidney injury in a mouse hindlimb ischemia-reperfusion model.
abstract: In this study, the relationship between the local imbalance of angiotensin converting enzymes ACE and ACE2 as well as Ang II and Ang (1-7) and renal injury was observed in the different genotypes mice subjected to tourniquet-induced ischemia-reperfusion on hind limbs. In wild-type mice, renal ACE expression increased while renal ACE2 expression decreased significantly after reperfusion, accompanied by elevated serum angiotensin II (Ang II) level and lowered serum angiotensin (1-7) (Ang (1-7)) level. However, renal Ang (1-7) also increased markedly while renal Ang II was elevated. Renal injury became evident after limb reperfusion, with increased malondialdehyde (MDA), decreased super-oxide dismutase (SOD) activity and increased serum blood urea nitrogen (BUN) and creatinine (Cr), compared to control mice. These mice also developed severe renal pathology including infiltration of inflammatory cells in the renal interstitium and degeneration of tubule epithelial cells. In ACE2 knock-out mice with ACE up-regulation, tourniquet-induced renal injury was significantly aggravated as shown by increased levels of MDA, BUN and Cr, decreased SOD activity, more severe renal pathology, and decreased survival rate, compared with tourniquet-treated wild-type mice. Conversely, ACE2 transgenic mice with normal ACE expression were more resistant to tourniquet challenge as evidenced by decreased levels of MDA, BUN and Cr, increased SOD activity, attenuated renal pathological changes and increased survival rate. Our results suggest that the deregulation of ACE and ACE2 plays an important role in tourniquet-induced renal injury and that ACE2 up-regulation to restore the proper ACE/ACE2 balance is a potential therapeutic strategy for kidney injury.
authors.affiliation: Department of Physiology, School of Basic Medical Science, Hebei United University, Tangshan, Hebei, China. ljkyxhljn@163.com
authors.forename: Xiu-hong
authors.initials: XH
authors.lastname: Yang
authors.forename: Yin-huan
authors.initials: YH
authors.lastname: Wang
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Wang
authors.forename: Ying-chao
authors.initials: YC
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.forename: Jun-ling
authors.initials: JL
authors.lastname: Gao
authors.forename: Lian-yuan
authors.initials: LY
authors.lastname: Zhang
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D000803:Angiotensin I / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D006614:Hindlimb / Q000098:blood supply*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000097:blood / Q000201:enzymology / Q000209:etiology; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014111:Tourniquets / Q000009:adverse effects*
chemical_list: D000804:Angiotensin II; D008315:Malondialdehyde; D000803:Angiotensin I; D003404:Creatinine; D013482:Superoxide Dismutase; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2