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Int J Biol Sci 2023; 19(16):5145-5159. doi:10.7150/ijbs.83906 This issue Cite

Research Paper

PTEN-induced kinase 1 exerts protective effects in diabetic kidney disease by attenuating mitochondrial dysfunction and necroptosis

Min-Ji Sung¹, Hyun-Ju An¹, Min Heui Ha¹, Seon Hwa Park², Hye Yun Jeong¹, Jihyun Baek¹, Sang Ho Lee², Yu Ho Lee^1✉, So-Young Lee^1✉

1. Devision of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
2. Devision of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, South Korea.

✉ Corresponding authors: Yu Ho Lee, M.D., Ph.D. Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, 13496, South Korea. Phone: +82-31-780-5025, Fax: +82-31-780-5219, E-mail: boryworknet. So-Young Lee, M.D., Ph.D. Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, 13496, South Korea. Phone: +82-31-780-5025, Fax: +82-31-780-5219, E-mail: ysy0119ac.kr. More

Abstract

Mitochondrial dysfunction plays a pivotal role in diabetic kidney disease initiation and progression. PTEN-induced serine/threonine kinase 1 (PINK1) is a core organizer of mitochondrial quality control; however, its function in diabetic kidney disease remains controversial. Here, we aimed to investigate the pathophysiological roles of PINK1 in diabetic tubulopathy, focusing on its effects on mitochondrial homeostasis and tubular cell necroptosis, which is a specialized form of regulated cell death. PINK1-knockout mice showed more severe diabetes-induced tubular injury, interstitial fibrosis, and albuminuria. The expression of profibrotic cytokines significantly increased in the kidneys of diabetic Pink1^-/- mice, which eventually culminated in aggravated interstitial fibrosis. Additionally, the knockdown of PINK1 in HKC-8 cells upregulated the fibrosis-associated proteins, and these effects were rescued by PINK1 overexpression. PINK1 deficiency was also associated with exaggerated hyperglycemia-induced mitochondrial dysfunction and defective mitophagic activity, whereas PINK1 overexpression ameliorated these negative effects and restored mitochondrial homeostasis. Mitochondrial reactive oxygen species triggered tubular cell necroptosis under hyperglycemic conditions, which was aggravated by PINK1 deficiency and improved by its overexpression. In conclusion, PINK1 plays a pivotal role in suppressing mitochondrial dysfunction and tubular cell necroptosis under high glucose conditions and exerts protective effects in diabetic kidney disease.

Keywords: PINK1, diabetic kidney disease, diabetic tubulopathy, mitochondria, necroptosis

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