Abstract
Chronic kidney disease (CKD) affects more than 10% of people worldwide and is a leading cause of death. However, the pathogenesis of CKD remains elusive. The oxidative stress and mitochondrial membrane potential were detected using Enzyme-linked immunosorbent assay and JC-1 assay. Co-immunoprecipitation, dual-luciferase assay, chromatin IP, RNA IP and RNA pull-down were used to validate the interactions among genes. Exploiting a H2O2-induced fibrosis model in vitro, PUM2 expression was upregulated in Human kidney 2 cell (HK-2) cells, along with reduced cell viability, enhanced oxidative stress, impaired mitochondrial potential, and upregulated expressions of fibrosis-associated proteins. While PUM2 knockdown reversed the H2O2-induced injury in HK-2 cells. Mechanically, Wnt/β-catenin pathway activated PUM2 transcription via TCF4. It was further identified that Wnt/β-catenin pathway inhibited YME1L expression through PUM2-mediated destabilizing of its mRNA. PUM2 aggravated H2O2-induced oxidative stress, mitochondrial dysfunction, and renal fibrosis in HK-2 cell via suppressing YME1L expression. Our study revealed that Wnt/β-catenin aggravated renal fibrosis by activating PUM2 transcription to repress YME1L-mediated mitochondrial homeostasis, providing novel insights and potential therapeutic targets for the treatment of kidney fibrosis.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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We would like to give our sincere gratitude to the reviewers for their constructive comments.
Funding
The study on the mechanism of Dickkopf-related protein 3 regulating the expression of mitochondrial protease YME1L to promote renal fibrosis; National Natural Science Foundation of China (No. 82160143); The Engineering Research Center of Kidney Disease in Jiangxi Province (No. 20164BCD40095).
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Conception of manuscript: Jianling Song, Yanxia Chen, Yan Chen, Minzi Qiu. Manuscript design and writing: Wenliu Xiang, Ben Ke, Xiangdong Fang. Manuscript reviewing and editing: all authors. All authors read and agreed to the final version of the manuscript.
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Song, J., Chen, Y., Chen, Y. et al. Wnt/β-catenin Pathway Aggravates Renal Fibrosis by Activating PUM2 Transcription to Repress YME1L-mediated Mitochondrial Homeostasis. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10756-y
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DOI: https://doi.org/10.1007/s10528-024-10756-y