Exogenous gene transmission of isocitrate dehydrogenase 2 mimics ischemic preconditioning protection

Alexander L. Kolb, Peter R. Corridon, Shijun Zhang, Weimin Xu, Frank Witzmann, Jason A. Collett, George J. Rhodes, Seth Winfree, Devin Bready, Zechariah J. Pfeffenberger, Jeremy M. Pomerantz, Takashi Hato, Glenn T. Nagami, Bruce Molitoris, David Basile, Simon J. Atkinson, Robert Bacallao

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Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. Asubstantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes inmitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP +-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine (P<0.05) observed in controls and increased the mitochondria membrane potential (P<0.05), maximal respiratory capacity (P<0.05), and intracellular ATP levels (P<0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemiareperfusion injury and mimics ischemic preconditioning.

Original languageEnglish (US)
Pages (from-to)1154-1164
Number of pages11
JournalJournal of the American Society of Nephrology
Issue number4
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Nephrology

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    Kolb, A. L., Corridon, P. R., Zhang, S., Xu, W., Witzmann, F., Collett, J. A., Rhodes, G. J., Winfree, S., Bready, D., Pfeffenberger, Z. J., Pomerantz, J. M., Hato, T., Nagami, G. T., Molitoris, B., Basile, D., Atkinson, S. J., & Bacallao, R. (2018). Exogenous gene transmission of isocitrate dehydrogenase 2 mimics ischemic preconditioning protection. Journal of the American Society of Nephrology, 29(4), 1154-1164. https://doi.org/10.1681/ASN.2017060675