کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6162826 | 1599147 | 2016 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
MicroRNA148b-3p inhibits mTORC1-dependent apoptosis in diabetes by repressing TNFR2 in proximal tubular cells
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کلمات کلیدی
TNF-α receptorFree fatty acids - اسیدهای چرب آِزادApoptosis - خزان یاختهایproximal tubular cell - سلول های لوله ای پروگزیمالTNF-α - فاکتور نکروز توموری آلفاMicroRNA - میکرو RNA Diabetic nephropathy - نفروپاتی دیابتیMammalian target of rapamycin complex 1 - هدف پستانداران مجتمع رپامایسین 1Hypoxia - هیپوکسیhigh glucose - گلوکز بالا یا قند بالا
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای کلیوی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Hypoxia causes proximal tubular cell damage in diabetes, even though proximal tubular cells have an adaptive system to combat hypoxia involving induction of hypoxia factor-1 (HIF-1) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). Here, we examined the interference effect of altered glucose and lipid metabolism on the hypoxia responses in proximal tubular cells. In culture, hypoxia alone induced HIF-1 and inhibited mTORC1, preventing death in proximal tubular cells. However, hypoxia with high glucose and palmitate increased mTORC1 activity and promoted apoptosis in proximal tubular cells, which was inhibited by pharmacological and genetic inactivation of mTORC1. Since inhibition of all mTORC1's physiological functions regulated by growth factors including insulin causes various adverse effects, we screened for a microRNA that can inhibit only pro-apoptotic effects of mTORC1 to discover a safe therapeutic target. This screen found microRNA-148b-3p was able to specifically inhibit mTORC1-dependent apoptosis in hypoxic proximal tubular cells exposed to high glucose and palmitate, without affecting insulin-dependent mTORC1 activation. Furthermore, tumor necrosis factor receptor (TNFR) 2 was the target of microRNA-148b-3p and its suppression inhibited apoptosis. Finally, enhanced apoptosis with TNFR2 overexpression was found in hypoxic and mTORC1-activated proximal tubular cells in diabetic rats. Thus, diabetes activated mTORC1 even in hypoxic proximal tubular cells, leading to apoptosis by reducing microRNA-148b-3p expression. Modulating this pathogenic pathway may be a novel therapy for proximal tubular cell damage in diabetes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Kidney International - Volume 90, Issue 6, December 2016, Pages 1211-1225
Journal: Kidney International - Volume 90, Issue 6, December 2016, Pages 1211-1225
نویسندگان
Shogo Kuwagata, Shinji Kume, Masami Chin-Kanasaki, Hisazumi Araki, Shinichi Araki, Jun Nakazawa, Takeshi Sugaya, Daisuke Koya, Masakazu Haneda, Hiroshi Maegawa, Takashi Uzu,