title: Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats.
abstract: BACKGROUND
  Diabetic nephropathy is a major risk of end-stage kidney disease. Many complex factors relate to the progression of diabetic nephropathy. Using nonobese type 2 diabetes model rats, we confirmed that oxidative stress was a crucial factor. Because recent studies suggest that vitamin D could suppress oxidative stress, we explored whether the active vitamin D analog, maxacalcitol, could also attenuate oxidative stress and prevent the progression of diabetic nephropathy.
  
  
  METHODS
  Diabetic rats aged 20 weeks were divided into 3 groups and treated with insulin, maxacalcitol, and vehicle. At age 30 weeks, blood and urine analyses, renal histology, immunohistochemistry, real-time polymerase chain reaction, and western blot were performed.
  
  
  RESULTS
  Although maxacalcitol reduced albuminuria and mesangial matrix expansion, no significant differences were observed in blood pressure and creatinine clearance among the 3 treatment groups. Systemic and intrarenal oxidative stress was reduced by maxacalcitol therapy. Expressions of nuclear factor-κB and nicotinamide adenine dinucleotide phosphate oxidase in the kidney also decreased in the insulin-treated and maxacalcitol-treated groups but increased in the vehicle-alone group. In addition, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) decreased and Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) increased in the vehicle-treated group; however, these expressions were restored in the maxacalcitol- and insulin-treated groups.
  
  
  CONCLUSIONS
  It is suggested that maxacalcitol attenuates the progression of diabetic nephropathy by suppression of oxidative stress and amelioration of the Nrf2-Keap1 pathway in nonobese type 2 diabetes without significant changes in blood pressure and glomerular filtration rate.
authors.affiliation: Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakai
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Keiji
authors.initials: K
authors.lastname: Kono
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Goto
authors.forename: Riko
authors.initials: R
authors.lastname: Kitazawa
authors.forename: Sohei
authors.initials: S
authors.lastname: Kitazawa
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
authors.forename: Masami
authors.initials: M
authors.lastname: Shinohara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishi
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000517:prevention & control*; D007328:Insulin / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D018167:Receptors, Calcitriol / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D018167:Receptors, Calcitriol; D019255:NADPH Oxidases; D002117:Calcitriol; C051883:maxacalcitol
keywords: Keap1; Nrf2; blood pressure; diabetic nephropathy; hypertension; oxidative stress; vitamin D.