Abstract
Diabetic nephropathy (DN), a serious complication of hyperglycemia, is one of the most common causes of end-stage renal disease (ESRD). Glomerular podocyte injury is a major mechanism that leads to DN. However, the mechanisms underlying podocyte injury are ambiguous. In this study, we sought to investigate the contribution of SET domain-containing protein 6 (SETD6) to the pathogenesis of podocyte injury induced by glucose (GLU) and palmitic acid (PA), as well as the underlying mechanisms. Our results showed that GLU and PA treatment significantly decreased SETD6 expression in mouse podocytes. Besides, Cell Counting Kit-8 (CCK-8) and flow cytometry assay demonstrated that silencing of SETD6 silence obviously enhanced cell viability, and suppressed apoptosis in GLU and PA-induced podocytes. We also discovered that downregulation of SETD6 suppressed GLU and PA-induced ROS generation and podocyte mitochondrial dysfunction. Nrf2-Keap1 signaling pathway was involved in the effect of SETD6 on mitochondrial dysfunction. Taken together, silencing of SETD6 protected mouse podocyte against apoptosis and mitochondrial dysfunction through activating Nrf2-Keap1 signaling pathway. Therefore these data provide new insights into new potential therapeutic targets for DN treatment.
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We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.
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Funding
The study was approved by Shaanxi Provincial Health and Family Planning Commission Scientific Research Fund (2016D018), the National Natural Sciences Foundation of China (81473010) and Shaanxi Province Key Research and Development Project fund (2018SF-173).
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XW, CXH and RL conceived and designed the study, and revised the draft; QLL and SW contributed to the acquisition, analyses, and interpretation of data; XW, QLL, DQK and ZL performed the cell culture and transfection experiments; XW, QLL, and YFG designed the experiments, performed data analyses, and drafted the manuscript. All authors contributed to writing the manuscript, reviewed and approving the final version. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
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Wang, X., Liu, Q., Kong, D. et al. Down-regulation of SETD6 protects podocyte against high glucose and palmitic acid-induced apoptosis, and mitochondrial dysfunction via activating Nrf2-Keap1 signaling pathway in diabetic nephropathy. J Mol Hist 51, 549–558 (2020). https://doi.org/10.1007/s10735-020-09904-6
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DOI: https://doi.org/10.1007/s10735-020-09904-6