title: Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts.
abstract: BACKGROUND
  Receptor for advanced glycation end products (RAGE) signaling pathway plays a vital role in diabetic cardiovascular complications. Calcitriol has been shown to exert various beneficial cardiovascular effects. The purpose of this study is to determine whether calcitriol can modulate RAGE expression, and study the potential mechanisms in diabetic hearts.
  
  
  METHODS
  Streptozotocin (65 mg/kg, intraperitoneal injection once) induced diabetic rats were treated with or without subcutaneous injections of calcitriol at a dose of 150 ng/kg/day for 4 weeks. Western blot was used to evaluate protein expressions of myocardial RAGE, TNF-α, p65 subunit of NF-κB (p65), α subunit of inhibitor of κB (IκBα), subunits of NADPH oxidase (NOX4 and p22(phox)), angiotensin II type 1 receptor (AT1R), TGF-β1, TGF-β receptor I, total and phosphorylated SMAD2/3 and ERK, matrix metalloproteinases 2 (MMP2), tissue inhibitors of metalloproteinases 2 (TIMP2) and procollagen I.
  
  
  RESULTS
  As compared to control, diabetic rats had increased expressions of cardiac RAGE, TNF-α, p22(phox), AT1R, and TGF-β1, which were significantly attenuated in the diabetic rats treated with calcitriol. Calcitriol-treated diabetic hearts also had lesser expressions of p-SMAD2/3 and p-ERK signaling than those of diabetic hearts. Moreover, diabetic hearts had increased expressions of MMP2 and procollagen I and decreased TIMP2. However, calcitriol reverted the diabetic effects in procollagen I but not in MMP2 or TIMP2.
  
  
  CONCLUSIONS
  Calcitriol decreased diabetic effects on RAGE and fibrosis, which may be caused by its modulation on AT1R and the anti-inflammatory and antioxidative potentials. Therefore, calcitriol may attenuate diabetic cardiomyopathy.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: yuhsunkao@gmail.com.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-I
authors.initials: TI
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Gi-Shih
authors.initials: GS
authors.lastname: Lien
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011921:Rats, Inbred WKY; D000067759:Receptor for Advanced Glycation End Products; D011945:Receptors, Angiotensin / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014815:Vitamins / Q000494:pharmacology
chemical_list: C524087:Agtrap protein, rat; D000975:Antioxidants; D024042:Collagen Type I; D000067759:Receptor for Advanced Glycation End Products; D011945:Receptors, Angiotensin; D011971:Receptors, Immunologic; D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014815:Vitamins; D019716:Tissue Inhibitor of Metalloproteinase-2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D002117:Calcitriol
keywords: Calcitriol; Diabetes mellitus; Heart; Receptor for advanced glycation end products; Vitamin D