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Redox Biol. 2017 Apr;11:297-311. doi: 10.1016/j.redox.2016.12.022. Epub 2016 Dec 21.

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1.

Author information

1
Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: xiaolizndx@163.com.
2
Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
3
Renal Division, Department of Medicine and Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4
Department of Endocrinology and Metabolism, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
5
Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.

Abstract

Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

KEYWORDS:

Diabetic kidney disease; Mitophagy; Mitoq; Tubular

PMID:
28033563
PMCID:
PMC5196243
DOI:
10.1016/j.redox.2016.12.022
[Indexed for MEDLINE]
Free PMC Article

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