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KCNQ1OT1/miR-18b/HMGA2 axis regulates high glucose-induced proliferation, oxidative stress, and extracellular matrix accumulation in mesangial cells

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Abstract

The dysregulated long noncoding RNAs (lncRNAs) are associated with the pathogenesis of diabetic nephropathy (DN). LncRNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) plays an important role in diabetes, but the role and mechanism of KCNQ1OT1 in DN are largely unknown. Serum samples were collected from 30 DN patients and normal volunteers. High glucose (HG)-challenged human mesangial cells (HMCs) were used as a cell model of DN. KCNQ1OT1, microRNA-18b (miR-18b), and high mobility group protein A2 (HMGA2) abundances were examined via quantitative reverse transcription polymerase chain reaction or western blot. Cell proliferation was assessed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide. Oxidative stress was assessed via the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and SOD2. Extracellular matrix (ECM) accumulation was investigated by the levels of fibronectin (FN), collagen I (Col I), and Col IV. The relationship between miR-18b and KCNQ1OT1 or HMGA2 was determined via dual-luciferase reporter analysis, RNA immunoprecipitation, and pull-down. KCNQ1OT1 expression was increased and miR-18b expression was decreased in DN patients and HG-challenged HMCs. miR-18b was targeted via KCNQ1OT1. Knockdown of KCNQ1OT1 weakened HG-caused proliferation, oxidative stress, and ECM accumulation of HMCs by increasing miR-18b. HMGA2 was targeted via miR-18b. miR-18b alleviated HG-induced cell proliferation, oxidative stress, and ECM accumulation by decreasing HMGA2. Silence of KCNQ1OT1 reduced HMGA2 expression via miR-18b. KCNQ1OT1 knockdown attenuated HG-induced proliferation, oxidative stress, and ECM accumulation of HMCs by regulating miR-18b/HMGA2 axis.

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  1. Jia Li and Mingming Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Navy 971 hospital, Qingdao, Shandong, 266000, China

    Jia Li

  2. Department of Endocrinology, Shandong Energy Zaozhuang Mining Group Central Hospital, Zaozhuang, Shandong, 277800, China

    Mingming Li

  3. Department of Emergency Medicine, Jining First People’s Hospital, Nanchi Mansion Building 2, Jining, Shandong, 272000, China

    Ling Bai

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Li, J., Li, M. & Bai, L. KCNQ1OT1/miR-18b/HMGA2 axis regulates high glucose-induced proliferation, oxidative stress, and extracellular matrix accumulation in mesangial cells. Mol Cell Biochem 476, 321–331 (2021). https://doi.org/10.1007/s11010-020-03909-1

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