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  • Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction.

Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction.

Free radical biology & medicine (2019-12-12)
Shu Li, Qisheng Lin, Xinghua Shao, Xuying Zhu, Jingkui Wu, Bei Wu, Minfang Zhang, Wenyan Zhou, Yijun Zhou, Haijiao Jin, Zhen Zhang, Chaojun Qi, Jianxiao Shen, Shan Mou, Leyi Gu, Zhaohui Ni
ABSTRACT

Mitophagy is a principle mechanism to degrade damaged mitochondria through PARK2-dependent or PARK2-independent pathway. Mitophagy has been identified to play an important role in acute kidney disease, whereas its role in renal fibrosis remains ill-defined. We sought to investigate the involvement and regulation of mitophagy in renal tubular epithelial cell(RTEC) injury and renal fibrosis after unilateral ureteral obstruction(UUO). Mitochondrial damageand mitochondrial reactive oxygen species (ROS) production was increased in kidney after obstruction of the left ureter. Mitophagy was increased in kidneys following UUO and HK-2 cells under hypoxia exposure, assessed by electron microscopy of mitophagosome, colocalization of MitotrackerRed-stained mitochondria and LC3 staining. The upregulation of PINK1, PARK2, and LC3 II in mitochondrial fraction was observed in the obstructed kidney and hypoxia-exposed HK-2 cells. Pink1 or Park2 gene deletion markedly increased mtROS production, mitochondrial damage, TGFβ1 expression in RTEC, and renal fibrosis in UUO. Mitochondrial recruitment of Drp1 was also induced after UUO. The Drp1 inhibitor, Mdivi-1, decreased mitochondrial PINK1, PARK2 and LC3II level, increased mtROS production both in vivo and in vitro, activated TGFβ1-Smad2/3 signaling in HK-2 cells under hypoxia and worsened renal fibrosis following UUO. The upregulation of TGFβ1 signaling in hypoxia-treated HK-2 cells due to PINK1 or PARK2 silencing, or worsened renal fibrosis after UUO due to Pink1-or Park2-KO mice was rescued by mitoTEMPO, a mitochondria-targeted antioxidant. The findings of this study suggest that Drp1-regulated PARK2-dependent mitophagy plays a critical role in hypoxia-induced renal tubular epithelial cell injury and renal fibrosis in UUO.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mdivi-1, ≥98% (HPLC), powder
Sigma-Aldrich
MISSION® esiRNA, targeting human PARK2
Sigma-Aldrich
MitoTEMPO, ≥98% (HPLC)