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Free Radic Biol Med. 2014 Feb;67:91-102. doi: 10.1016/j.freeradbiomed.2013.10.811. Epub 2013 Oct 24.

Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1-Nrf2, Tgfβ1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice.

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  • 1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
  • 2State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China; School of Nursing, The Third Military Medical University, Chongqing, 400038, China. Electronic address: luoyuhlgl@gmail.com.
  • 3School of Life Sciences and Fujian Key Laboratory of Preventive Veterinary Medicine and Biotechnology, Longyan University, Longyan, 364000, China.
  • 4School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
  • 5State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China. Electronic address: yuanli@xmu.edu.cn.
  • 6State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China; Fujian Provincial Transgenic Core, Laboratory Animal Center, Xiamen University, Xiang'an, Xiamen, 361102, China. Electronic address: jyqy2008@gmail.com.

Abstract

Aberrant regulation in oxidative stress, fibrogenesis, and the epithelial-mesenchymal transition (EMT) in renal cells under hyperglycemic conditions contributes significantly to the onset and progression of diabetic nephropathy. The mechanisms underlying these hyperglycemia-induced dysregulations, however, have not been clearly elucidated. Herein, we report that aldose reductase is capable of regulating the expression of miR-200a-3p/141-3p negatively in renal mesangial cells. MiR-200a-3p/141-3p, in turn, act to target Keap1, Tgfβ2, fibronectin, and Zeb2 directly and regulate Tgfβ1 and Nrf2 indirectly under high-glucose conditions, resulting in profound dysregulations in Keap1-Nrf2, Tgfβ1/2, and Zeb1/2 signaling. In vivo in streptozotocin-induced diabetic mice, we found that aldose reductase deficiency caused significant elevations in miR-200a-3p/141-3p in the renal cortex, which were accompanied by a significant downregulation of Keap1, Tgfβ1/2, and fibronectin but significant upregulation of Nrf2. Moreover, in vivo administration of inhibitors of miR-200a-3p in diabetic animals significantly exacerbated cortical and glomerular fibrogenesis and increased urinary albumin excretion, tightly linking dysregulated miR-200a-3p with the development of diabetic nephropathy. Collectively, our results reveal a novel mechanism whereby hyperglycemia induces aldose reductase to regulate renal expression of miR-200a-3p/141-3p to coordinately control hyperglycemia-induced renal oxidative stress, fibrogenesis, and the EMT. Our novel findings also suggest that inhibition of aldose reductase and in vivo renal cortical restoration of miR-200a-3p/141-3p or their combination are very promising avenues for the development of therapeutic strategies or drugs against diabetic nephropathy.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Aldose reductase; Antioxidant defense; Epithelial–mesenchymal transition; Fibrogenesis; Free radicals; miR-200a-3p/141-3p

PMID:
24161443
[PubMed - indexed for MEDLINE]
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