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

Communications biology (2021-01-06)
Mitsuo Kato, Maryam Abdollahi, Ragadeepthi Tunduguru, Walter Tsark, Zhuo Chen, Xiwei Wu, Jinhui Wang, Zhen Bouman Chen, Feng-Mao Lin, Linda Lanting, Mei Wang, Janice Huss, Patrick T Fueger, David Chan, Rama Natarajan
RÉSUMÉ

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.

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Magnesium methyl carbonate solution, 2.0 M in DMF
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Fis1