title: In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway.
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)2D3inhibited the proliferation of mesangial cells induced by hyperglycemia. 1,25(OH)2D3also 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)2D3treatment. The phosphorylation of mammalian target of rapamycin was reduced by 1,25(OH)2D3treatment. Vitamin D receptor gene silencing blocked all of the above results. The current study demonstrates that 1,25(OH)2D3can 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)2D3occurs partly through the DDIT4/TSC2/mTOR pathway.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Hang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Chongqing Armed Corps Police Hospital, Chongqing, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Huili
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Baolan
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Zesong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China. deng_huacong@126.com.
authors.forename: Huacong
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002117:Calcitriol / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D020868:Gene Silencing; D007668:Kidney / Q000187:drug effects; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D014280:Triglycerides; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; D058570:TOR Serine-Threonine Kinases; D002117:Calcitriol; D002118:Calcium
keywords: DDIT4; Diabetic nephropathy; Proliferation; Vitamin D; mTOR