Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats

Am J Hypertens. 2014 Apr;27(4):586-95. doi: 10.1093/ajh/hpt160. Epub 2013 Sep 11.


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.

Keywords: Keap1; Nrf2; blood pressure; diabetic nephropathy; hypertension; oxidative stress; vitamin D..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / prevention & control
  • Animals
  • Antioxidants / metabolism
  • Calcitriol / analogs & derivatives*
  • Calcitriol / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / prevention & control*
  • Insulin / therapeutic use
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Kidney Glomerulus / pathology
  • Male
  • NADPH Oxidases / biosynthesis
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Rats
  • Receptors, Calcitriol / biosynthesis


  • Antioxidants
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Receptors, Calcitriol
  • NADPH Oxidases
  • Calcitriol
  • maxacalcitol