title: AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia/reperfusion.
abstract: We recently reported that the expression of the synaptic form of acetylcholinesterase (AChE) is induced during apoptosis in various cell types in vitro. Here, we provide evidence to confirm that AChE is expressed during ischemia-reperfusion (I/R)-induced apoptosis in vivo. Renal I/R is a major cause of acute renal failure (ARF), resulting in injury and the eventual death of renal cells due to a combination of apoptosis and necrosis. Using AChE-deficient mice and AChE inhibitors, we investigated whether AChE deficiency or inhibition can protect against apoptosis caused by I/R in a murine kidney model. Unilateral clamping of renal pedicles for 90 min followed by reperfusion for 24 h caused significant renal dysfunction and injury. Both genetic AChE deficiency and chemical inhibition of AChE (provided by huperzine A, tacrine and donepezil) significantly reduced the biochemical and histological evidence of renal dysfunction following I/R. Activation of caspases-8, -9, -12, and -3 in vivo were prevented and associated with reduced levels of cell apoptosis and cell death. A further investigation also confirmed that AChE deficiency down-regulated p53 induction and phosphorylation at serine-15, and decreased the Bax/Bcl-2 ratio during I/R. In conclusion, our study demonstrates that AChE may be a pro-apoptotic factor and the inhibition of AChE reduces renal I/R injury. These findings suggest that AChE inhibitors may represent a therapeutic strategy for protection against ischemic acute renal failure.
authors.affiliation: Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, China. wyye@sibs.ac.cn
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Ye
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Gong
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Xuejin
authors.initials: X
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhao
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000096:biosynthesis / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D004790:Enzyme Induction; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003404:Creatinine; D000110:Acetylcholinesterase; D020169:Caspases