title: 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.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Bi
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Song
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: School of Life Sciences and Fujian Key Laboratory of Preventive Veterinary Medicine and Biotechnology, Longyan University, Longyan, 364000, China.
authors.forename: Longxin
authors.initials: L
authors.lastname: Qiu
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
authors.forename: Longping
authors.initials: L
authors.lastname: Wen
authors.affiliation: State 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.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: State 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.
authors.forename: James Y
authors.initials: JY
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000449:Aldehyde Reductase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D007672:Kidney Cortex / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C543718:Mirn141 microRNA, mouse; C543719:Mirn200 microRNA, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C519422:ZEB1 protein, mouse; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000449:Aldehyde Reductase
keywords: Aldose reductase; Antioxidant defense; Epithelial–mesenchymal transition; Fibrogenesis; Free radicals; miR-200a-3p/141-3p