Regulation of mitochondrial dynamics by Dynamin- related protein-1 in acute cardiorenal syndrome

Maki Sumida, Kent Doi, Emi Ogasawara, Tetsushi Yamashita, Yoshifumi Hamasaki, Taro Kariya, Eiki Takimoto, Naoki Yahagi, Masaomi Nangaku, Eisei Noiri

Research output: Contribution to journalArticle

Abstract

Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich inmitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography,were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in themitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

Original languageEnglish (US)
Pages (from-to)2378-2387
Number of pages10
JournalJournal of the American Society of Nephrology
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Sumida, M., Doi, K., Ogasawara, E., Yamashita, T., Hamasaki, Y., Kariya, T., Takimoto, E., Yahagi, N., Nangaku, M., & Noiri, E. (2015). Regulation of mitochondrial dynamics by Dynamin- related protein-1 in acute cardiorenal syndrome. Journal of the American Society of Nephrology, 26(10), 2378-2387. https://doi.org/10.1681/ASN.2014080750