PMID- 31494242 OWN - NLM STAT- MEDLINE DCOM- 20200902 LR - 20211204 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 145 DP - 2019 Dec TI - Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/beta-TrcP/Nrf2 pathway. PG - 118-135 LID - S0891-5849(19)31054-8 [pii] LID - 10.1016/j.freeradbiomed.2019.09.003 [doi] AB - Bergenin, a plant polyphenol, has been reported to lower the blood glucose level and ameliorate kidney function in streptozotocin (STZ)-induced diabetic rats. Herein, its protective effect on diabetic nephropathy (DN) was explored in view of extracellular matrix (ECM) generation in glomerular mesangial cells. Glomerular mesangial cells were treated with high glucose, and Q-PCR as well as western blot were used to determine the expression of ECM. To establish the participation and role of mammalian target of rapamycin (mTOR) and nuclear factor erythroid-derived 2-related factor 2 (Nrf2) in ECM generation, a combination of l-leucine (activator of mTOR) and Nrf2 shRNA transfection were performed, respectively. Moreover, a DN model was established in mice using high-glucose/high-fat diet and STZ. Bergenin impeded the generation of TGF-beta1 and ECM, decreased the levels of intracellular superoxide anion and hydrogen peroxide, and increased the activity of antioxidant enzymes in the glomerular mesangial cells (HBZY-1 and HRMC cells) treated with high glucose. The inhibition of ECM generation by bergenin was dependent on the down-regulation of oxidative stress as confirmed via a superoxide overexpression system. The activation of Nrf2 was required for bergenin to inhibit the oxidative stress and ECM generation. Moreover, bergenin was found to inhibit the phosphorylation of mTOR, which is located at the upstream of Nrf2. Bergenin did not interfere with the expression of Nrf2 mRNA and Keap1 (the classic degradation control factor of Nrf2), but markedly inhibited the protein expression of the beta-TrcP, an effect which could be abolished by l-leucine. In DN model mice, l-leucine diminished the ability of bergenin to reduce the levels of superoxide anion, hydrogen peroxide and ECM, which contributed to the eradication of the ameliorative effect of bergenin on nephropathy. Bergenin can inhibit glucose-induced ECM production in glomerular mesangial cells through the down-regulation of oxidative stress via the mTOR/beta-TrcP/Nrf2 pathway, and it might be a candidate drug for the prevention and treatment of DN. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Qiao, Simiao AU - Qiao S AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Liu, Rui AU - Liu R AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Lv, Changjun AU - Lv C AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Miao, Yumeng AU - Miao Y AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Yue, Mengfan AU - Yue M AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Tao, Yu AU - Tao Y AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Wei, Zhifeng AU - Wei Z AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. FAU - Xia, Yufeng AU - Xia Y AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address: yfxiacpu@126.com. FAU - Dai, Yue AU - Dai Y AD - Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address: yuedaicpu@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190905 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Benzopyrans) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (beta-Transducin Repeat-Containing Proteins) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - L84RBE4IDC (bergenin) SB - IM MH - Animals MH - Benzopyrans/*pharmacology MH - Diabetic Nephropathies/*drug therapy/genetics/pathology MH - Extracellular Matrix/drug effects/genetics MH - Humans MH - Mesangial Cells MH - Mice MH - Mice, Inbred NOD MH - NF-E2-Related Factor 2/*genetics MH - Oxidative Stress/drug effects MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*genetics MH - beta-Transducin Repeat-Containing Proteins/*genetics OTO - NOTNLM OT - Bergenin OT - Diabetic nephropathy OT - Extracellular matrix OT - Glomerular mesangial cells OT - Oxidative stress EDAT- 2019/09/09 06:00 MHDA- 2020/09/04 06:00 CRDT- 2019/09/09 06:00 PHST- 2019/06/24 00:00 [received] PHST- 2019/08/30 00:00 [revised] PHST- 2019/09/03 00:00 [accepted] PHST- 2019/09/09 06:00 [pubmed] PHST- 2020/09/04 06:00 [medline] PHST- 2019/09/09 06:00 [entrez] AID - S0891-5849(19)31054-8 [pii] AID - 10.1016/j.freeradbiomed.2019.09.003 [doi] PST - ppublish SO - Free Radic Biol Med. 2019 Dec;145:118-135. doi: 10.1016/j.freeradbiomed.2019.09.003. Epub 2019 Sep 5.