کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8270854 | 1534975 | 2014 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
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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کلمات کلیدی
GSHSTZLNAPKCARIZEB1/2NQO1shRNANrf2GCLCMREACVR2BmicroRNA recognition elementGSTA1ECM3′-untranslated region - 3'-ناحیه ترجمه نشده3′UTR - 3'UTRkeap1 - buy1E-cad - E-CADE-cadherin - E-CadherinAr/Ar - On / Arshort hairpin RNA - RNA موی سر کوتاهROS - ROSAldose reductase - آلدووز ردوکتازstreptozotocin - استرپتوزوتوسینperiodic acid–Schiff - اسید فسفریک SchiffLocked Nucleic Acid - اسید نوکلئیک قفل شدهEMT - تکنسین فوریتهای پزشکیAntioxidant defense - دفاع آنتی اکسیدانFree radicals - رادیکال آزادFibronectin - فیبرونکتینFibrogenesis - فیبروژنزExtracellular matrix - ماتریکس خارج سلولیAldose reductase inhibitor - مهار کننده آلدوز ردوکتازknockout - ناکاوتDiabetic nephropathy - نفروپاتی دیابتیPAS - نهwild-type - نوع وحشیKelch-like ECH-associated protein 1 - پروتئین مرتبط با ECH کلچ 1Protein kinase C - پروتئین کیناز سیreduced glutathione - کاهش گلوتاتیونCollagen IV - کلاژن IVGlutamate–cysteine ligase catalytic subunit - کلوتامین کاتالیستی لیگاز گلوتامات-سیتئینEpithelial–mesenchymal transition - گذار اپیتلیال-مزانشیمیReactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 67, February 2014, Pages 91-102
Journal: Free Radical Biology and Medicine - Volume 67, February 2014, Pages 91-102
نویسندگان
Jie Wei, Ye Zhang, Yu Luo, Zhen Wang, Shulin Bi, Dan Song, Yuan Dai, Tao Wang, Longxin Qiu, Longping Wen, Li Yuan, James Y. Yang,