Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 473, Issue -, Pages 31-43Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2017.12.012
Keywords
Diabetic nephropathy; Mesangial cells; Apoptosis; mTOR signaling; Oxidative stress
Categories
Funding
- National Natural Science Foundation of China [81400741, 81473257]
- Qing Lan project
- Natural Science Foundation of Jiangsu Province [BK20151155]
- 333 Foundation of Jiangsu Province [BRA2015329]
- Key Natural Science Foundation of Jiangsu Higher Education Institutions of China [15KJA310005]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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Glomerular mesangial cell (MC) apoptosis is one of the important mechanisms of glomerulosclerosis, which induces an increased severity of albuminuria and promotes the development of diabetic nephropathy (DN). However, the mechanism by which high glucose (HG) induces MCs apoptosis is not fully understood. In the present study, we investigated the effects of mTOR signalling on apoptosis in cultured MCs exposed to HG and in type I diabetes, and tried to clarify the specific mechanisms underlying these effects. In vitro, exposure of MCs to HG stimulated ROS production, decreased the antioxidant enzyme superoxide dismutase (SOD) activity and glutathione (GSH) level, increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, upregulated P53 expression and Bax/Bcl-2 ratio and enhanced cleavage of caspase 3, resulting in an increase in programmed cell death. Pretreatment of the cells with rapamycin ameliorated oxidative stress, reduced the number of apoptotic cells induced by HG and caused the downstream effects of mTOR activation. In vivo, compared with control rats, diabetic rats had more apoptotic cells in glomeruli. Induction of diabetes increased the level of MDA and NADPH oxidase activity, decreased the SOD activity and GSH level, elevated the Bax/Bcl ratio and P53 expression and activated caspase 3. mTOR inhibitor rapamycin treatment prevented these changes further alleviated albuminuria and improved renal function. Taken together, our data suggest that mTOR plays a key role in mediating ROS-induced MC apoptosis in diabetic nephropathy, and these effects have been associated with the promotion of ROS production by upregulating the antioxidant enzyme and downregulating the NADPH oxidase activity. (C) 2017 Elsevier B.V. All rights reserved.
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