miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

Creators: Kato, Mitsuo; Abdollahi, Maryam; Tunduguru, Ragadeepthi; Tsark, Walter; Chen, Zhuo; Wu, Xiwei; Wang, Jinhui; Chen, Zhen Bouman; Lin, Feng-Mao; Lanting, Linda; Wang, Mei; Huss, Janice; Fueger, Patrick T.; Chan, David; Natarajan, Rama

Abstract

Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.

Additional Information

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 27 May 2020; Accepted 23 November 2020; Published 04 January 2021. These studies were supported by grants from the National Institutes of Health (NIH), R01 DK081705, R01 DK058191, and R01 HL106089 (to R.N.), the Wanek Family Project for the Cure of Type 1 diabetes at City of Hope (to R.N. and M.K.), R01HL145170 (to Z.B.C.), the American Diabetes Association ADA-1-18-IBS-103 (to J.H.) and a Postdoctoral fellowship from the Larry L. Hillblom Foundation (to R.T.). We are grateful to members of the Natarajan laboratory for helpful discussions. Research reported in this publication included work performed in the following Cores: Pathology Research Services, Integrative Genomics and Bioinformatics, and Comprehensive Metabolic Phenotyping, supported by the National Cancer Institute of the NIH under award number P30CA33572, as well as the Animal Resource Center, Transgenic/Knockout Animal and Electron Microscopy (EM/AFM) Cores at City of Hope. We are grateful to Dr. Zhuo Li and Ricardo Zerda Noriega of the EM/AFM Core at City of Hope for their help with preparation of samples for TEM and the imaging. Data availability: All sequencing datasets generated in this study have been deposited into GEO with GEO #s GSE142596, GSE142597, and GSE142598. The source data underlying the graphs in figures are provided in Supplementary Data 1 and 2. Full gel is shown in Supplementary Information. All relevant data are available from the authors upon request. These authors contributed equally: Mitsuo Kato, Maryam Abdollahi. Author Contributions: M.K., M.A., and R.N. designed research. M.K., M.A., M.W., R.T., and L.L. performed research. M.K., M.A., Z.C., R.T, and M.W. analyzed the data. W.T. produced the miR-379KO mice. F.-M.L., M.K., Z.B.C., and Z.C. analyzed RNA-seq and hybrid-seq results. D.C. helped with the mitochondria function experiments, J.H. with the Seahorse experiments, and P.T.F. with the mouse metabolic phenotyping. M.K., M.A., and R.N. wrote and edited the manuscript. All authors have read and discussed the manuscript. The authors declare no competing interests.

Errata

Kato, M., Abdollahi, M., Tunduguru, R. et al. Publisher Correction: miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1. Commun Biol 4, 175 (2021). https://doi.org/10.1038/s42003-021-01691-4

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