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In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway

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Abstract

We investigated whether 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) could improve early diabetic nephropathy through the DNA-damage-inducible transcript 4/tuberous sclerosis 2/mammalian target of rapamycin pathway. Rat mesangial cells were cultured in media containing normal glucose or high glucose and were treated with or without 1,25(OH)2D3. Mesangial cells proliferation was measured. Streptozotocin-induced diabetic rats were injected intravenously with a recombinant lentivirus against the rat vitamin D receptor gene. Urinary and serum albumin, fasting plasma glucose, serum triglyceride, total cholesterol, calcium, parathyroid hormone and serum 25-dihydroxy-vitamin D (25(OH)D) levels, mean glomerular volume, glomerular basement membrane thickness and total kidney volume were determined. The expressions of vitamin D receptor, DNA-damage-inducible transcript 4, and mammalian target of rapamycin were measured. 1,25(OH)2D3 inhibited the proliferation of mesangial cells induced by hyperglycemia. 1,25(OH)2D3 also significantly reduced albumin excretion, mean glomerular volume, glomerular basement membrane, and total kidney volume in rats with diabetic nephropathy. The expression of DNA-damage-inducible transcript 4 was elevated by 1,25(OH)2D3 treatment. The phosphorylation of mammalian target of rapamycin was reduced by 1,25(OH)2D3 treatment. Vitamin D receptor gene silencing blocked all of the above results. The current study demonstrates that 1,25(OH)2D3 can effectively inhibit mesangial cells proliferation induced by hyperglycemia, thus suppressing the development of diabetic nephropathy. This study also shows that the nephron-protective effect of 1,25(OH)2D3 occurs partly through the DDIT4/TSC2/mTOR pathway.

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Acknowledgments

This study was supported by research grants from the National Nature Science Foundation of China (81070639, 81270911, 30771038, and 30570744) and National Key Clinical Specialties Construction Program of China. We specially thank the technical support from Laboratory of Lipid and Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.

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  1. Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China

    Hang Wang, Hua Qu, Huili Wei, Baolan ji, Zesong Yang, Jing Wu, Qin He, Yuanyuan Luo, Dan Liu, Yang Duan, Fang Liu & Huacong Deng

  2. Department of Nephrology, Chongqing Armed Corps Police Hospital, Chongqing, P.R. China

    Jianmin Wang

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Wang, H., Wang, J., Qu, H. et al. In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway. Endocrine 54, 348–359 (2016). https://doi.org/10.1007/s12020-016-0999-1

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