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Upregulation of UHRF1 Promotes PINK1-mediated Mitophagy to Alleviates Ferroptosis in Diabetic Nephropathy

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Abstract

Diabetic nephropathy (DN) is a common diabetic complication. Studies show that mitophagy inhibition induced-ferroptosis plays a crucial role in DN progression. UHRF1 is associated with mitophagy and is highly expression in DN patients, however, the effect of UHRF1 on DN is still unclear. Thus, in this study, we aimed to investigate whether UHRF1 involves DN development by the mitophagy/ferroptosis pathway. We overexpressed UHRF1 using an adeno-associated virus 9 (AAV9) system in high-fat diet/streptozotocin-induced diabetic mice. Renal function index, pathological changes, mitophagy factors, and ferroptosis factors were detected in vivo. High-glucose cultured human renal proximal tubular (HK-2) cells were used as in vitro models to investigate the mechanism of UHRF1 in DN. We found that diabetic mice exhibited kidney damage, which was alleviated by UHRF1 overexpression. UHRF1 overexpression promoted PINK1-mediated mitophagy and inhibited the expression of thioredoxin interacting protein (TXNIP), a factor associated with mitochondrial dysfunction. Additionally, UHRF1 overexpression alleviated lipid peroxidation and free iron accumulation, and upregulated the expression of GPX4 and Slc7a11, indicating the inhibition effect of UHRF1 overexpression on ferroptosis. We further investigated the mechanism of UHRF1 in the mitophagy/ferroptosis pathway in DN. We found that UHRF1 overexpression promoted PINK1-mediated mitophagy via inhibiting TXNIP expression, thus suppressing ferroptosis. These findings confirmed that upregulation of UHRF1 expression alleviates DN, indicating that UHRF1 has a reno-protective effect against DN.

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DATA AVAILABILITY

The data in this study is available from the corresponding author upon reasonable request.

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Funding

This research was funded by the National Natural Science Foundation of China (Grant No. 81570746 to G. Qin), the Medical Science and Technology Cooperation Project of Henan Province (Grant No. 2018020019 to H. Ji), the Medical Science and Technology Project of Henan Province (Grant No. 212102310196 to H. Ji).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Hongfei Ji, Yanyan Zhao, Xiaojun Ma, Lina Wu, Feng Guo, Fengjuan Huang, Yi Song, Jiao Wang & Guijun Qin

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Contributions

H. F. J. and G. J. Q. conceived the presented ideas. H. F. J., Y. Y. Z., X. J. M. and L. N. W. performed experiments. H. F. J., F. G., F. J. H., Y. S. and J. W. analyzed the data. H. F. J. and G. J. Q. drafted the paper. All authors have read and approved the final version of the paper.

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Correspondence to Guijun Qin.

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Ji, H., Zhao, Y., Ma, X. et al. Upregulation of UHRF1 Promotes PINK1-mediated Mitophagy to Alleviates Ferroptosis in Diabetic Nephropathy. Inflammation 47, 718–732 (2024). https://doi.org/10.1007/s10753-023-01940-0

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