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AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia/reperfusion

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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.

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Abbreviations

AChE:

Acetylcholinesterase

AChEIs:

Acetylcholinesterase inhibitors

AD:

Alzheimer’s disease

ARF:

Acute renal failure

GSK 3:

Glycogen synthase kinase 3

I/R:

Ischemia-reperfusion

JNK:

The c-Jun-N-terminal kinase

TUNEL:

Terminal deoxynucleotidyltransferase-mediated dUTP nick-end-labeling

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Acknowledgments

This work was supported in part by grants from the Major State Basic Research Development Program of China (973 Program, No. 2007CB947901),the Third Phase Creative Program of Chinese Academy of Sciences (No. KSCX1-YW-R-13), the National Natural Science Foundation of China (Nos. 30971481 and 30623003).

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China

    Weiyuan Ye, Xiaowen Gong, Jing Xie, Jun Wu, Xuejin Zhang, Qi Ouyang, Xiaolin Zhao & Xuejun Zhang

  2. Department of Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Yufang Shi

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  1. Weiyuan Ye
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  2. Xiaowen Gong
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Correspondence to Xuejun Zhang.

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Weiyuan Ye and Xiaowen Gong have contributed equally to this article.

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Ye, W., Gong, X., Xie, J. et al. AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia/reperfusion. Apoptosis 15, 474–487 (2010). https://doi.org/10.1007/s10495-009-0438-3

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  • DOI: https://doi.org/10.1007/s10495-009-0438-3

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