Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts

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-alpha, p65 subunit of NF-kappa B (p65), a subunit of inhibitor of kappa B (I kappa Ba), subunits of NADPH oxidase (NOX4 and p22(phox)), angiotensin II type 1 receptor (AT1R), TGF-beta 1, TGF-beta 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-alpha, p22phox, AT1R, and TGF-beta 1, 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. (c) 2014 Elsevier Ireland Ltd. All rights reserved.