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The Vitamin D Receptor Activator Maxacalcitol Provides Cardioprotective Effects in Diabetes Mellitus

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Abstract

Purpose

Recent reports showed a significant association between vitamin D levels and cardiovascular disease events and mortality. In the current study, we investigated the effect of the vitamin D receptor activator maxacalcitol (OCT) on cardiac damage in a rat model of type 2 diabetes.

Methods

At 20 weeks of age, the rats were divided into three groups: vehicle-treated (DM), insulin-treated (INS) and OCT-treated (OCT). At 30 weeks, the rats were sacrificed and urinary and blood biochemical analyses and cardiac histological and immunohistochemical analyses were performed. To evaluate the effect of OCT on the renin-angiotensin system, we performed a further study using aliskiren (ALS). At 20 weeks, the diabetic rats were divided into two groups: the ALS-treated group (ALS) and the ALS plus OCT-treated group (ALS + OCT), and we evaluated the renin-angiotensin system (RAS) and cardiac lesions at 30 weeks.

Results

At 30 weeks, despite comparable blood pressure and renal function, heart volume, intracardiac oxidative stress by immunohistological analysis, cardiac and perivascular fibrosis and urinary excretion of 8-hydroxydeoxyguanosine and serum N-terminal pro-brain natriuretic peptide levels were significantly decreased in the OCT group compared to the DM group. mRNA expressions of dihydronicotinamide adenine dinucleotide phosphate (NADPH) p47 subunit and cardiac injury-related markers in the heart were also significantly decreased in the OCT group compared to the DM group. The cardioprotective effect of OCT was preserved even in the context of RAS inhibition.

Conclusion

Our results suggest that OCT prevents the development of cardiac damage in DM, independent of RAS inhibition.

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References

  1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.

    Article  CAS  PubMed  Google Scholar 

  2. Ninomiya T, Kiyohara Y, Kubo M, et al. Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama Study. Kidney Int. 2005;68:228–36.

    Article  PubMed  Google Scholar 

  3. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    Article  CAS  PubMed  Google Scholar 

  4. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–17.

    Article  CAS  PubMed  Google Scholar 

  5. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin–angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026–33.

    Article  CAS  PubMed  Google Scholar 

  6. Asanuma H, Minamino T, Sanada S, et al. ß-Adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts. Circulation. 2004;109:2773–9.

    Article  CAS  PubMed  Google Scholar 

  7. Wang R, Miura T, Harada N, et al. Pleiotropic effects of the beta-adrenoceptor blocker carvedilol on calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. J Pharmacol Exp Ther. 2006;318:45–52.

    Article  CAS  PubMed  Google Scholar 

  8. Packer M, Fowler MB, Roecker EB, et al. Carvedilol prospective randomized cumulative survival (COPERNICUS) study group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–9.

    Article  PubMed  Google Scholar 

  9. Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357:266–81.

    Article  CAS  PubMed  Google Scholar 

  10. Mehrotra R, Kermah DA, Salusky IB, et al. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Kidney Int. 2009;76:977–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med. 2010;51:228–33.

    Article  CAS  PubMed  Google Scholar 

  12. Chitalia N, Ismail T, Tooth L, et al. Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS One. 2014;9, e91363.

    Article  PubMed Central  PubMed  Google Scholar 

  13. de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomized controlled trial. Lancet. 2010;376:1543–51.

    Article  PubMed  Google Scholar 

  14. Kong J, Kim GH, Wei M, et al. Therapeutic effects of vitamin D analogs on cardiac hypertrophy in spontaneously hypertensive rats. Am J Pathol. 2010;177:622–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Panizo S, Barrio-Vázquez S, Naves-Díaz M, et al. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol Dial Transplant. 2013;28:2735–44.

    Article  CAS  PubMed  Google Scholar 

  16. Kirii K, Mizoue T, Iso H, et al. Japan public health center-based prospective study group. Calcium, vitamin D and dairy intake in relation to type 2 diabetes risk in a Japanese cohort. Diabetologia. 2009;52:2542–50.

    Article  CAS  PubMed  Google Scholar 

  17. Svoren BM, Volkening LK, Wood JR, Laffel LM. Significant vitamin D deficiency in youth with type 1 diabetes mellitus. J Pediatr. 2009;154:132–4.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Fujii H, Nishijima F, Goto S, et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol Dial Transplant. 2009;24:2089–95.

    Article  CAS  PubMed  Google Scholar 

  19. Fujii H, Kono K, Nakai K, et al. Oxidative and nitrosative stress and progression of diabetic nephropathy in type 2 diabetes. Am J Nephrol. 2010;31:342–52.

    Article  CAS  PubMed  Google Scholar 

  20. Lemmilä S, Saha H, Virtanen V, Ala-Houhala I, Pasternack A. Effect of intravenous calcitriol on cardiac systolic and diastolic function in patients on hemodialysis. Am J Nephrol. 1998;18:404–10.

    Article  PubMed  Google Scholar 

  21. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674–84.

    Article  CAS  PubMed  Google Scholar 

  22. Wang AY, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD—The OPERA trial. J Am Soc Nephrol. 2014;25:175–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Scragg R, Sowers M, Bell C, Third National Health and Nutrition Examination Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the third national health and nutrition examination survey. Diabetes Care. 2004;27:2813–8.

    Article  CAS  PubMed  Google Scholar 

  24. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.

    Article  CAS  PubMed  Google Scholar 

  25. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213–23.

    Article  PubMed  Google Scholar 

  26. Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med. 2008;121:748–57.

    Article  PubMed  Google Scholar 

  27. Noyan T, Balaharoğlu R, Kömüroğlu U. The oxidant and antioxidant effects of 25-hydroxyvitamin D3 in liver, kidney and heart tissues of diabetic rats. Clin Exp Med. 2005;5:31–6.

    Article  CAS  PubMed  Google Scholar 

  28. Nakai K, Fujii H, Kono K, et al. Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. Am J Hypertens. 2014;27:586–95.

    Article  CAS  PubMed  Google Scholar 

  29. Andress DL. Vitamin D, in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006;69:33–43.

    Article  CAS  PubMed  Google Scholar 

  30. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25:320–5.

    Article  CAS  PubMed  Google Scholar 

  31. Inoue K, Matsui I, Hamano T, et al. Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3. Lab Invest. 2012;92:1686–97.

    Article  CAS  PubMed  Google Scholar 

  32. Molkentin JD. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res. 2004;63:467–75.

    Article  CAS  PubMed  Google Scholar 

  33. Muslin AJ. MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond). 2008;115:203–18.

    Article  CAS  Google Scholar 

  34. Vega RB, Bassel-Duby R, Olson EN. Control of cardiac growth and function by calcineurin signaling. J Biol Chem. 2003;278:36981–4.

    Article  CAS  PubMed  Google Scholar 

  35. Chen S, Law CS, Grigsby CL, et al. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation. 2011;124:1838–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–408.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119:2545–52.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Cha H, Jeong HJ, Jang SP, et al. Parathyroid hormone accelerates decompensation following left ventricular hypertrophy. Exp Mol Med. 2010;42:61–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Fujii H, Kim JI, Abe T, Umezu M, Fukagawa M. Relationship between parathyroid hormone and cardiac abnormalities in chronic dialysis patients. Intern Med. 2007;46:1507–12.

    Article  PubMed  Google Scholar 

  40. Choi KM, Zhong Y, Hoit BD, et al. Defective intracellular Ca(2+) signaling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol Heart Circ Physiol. 2002;283:H1398–408.

    Article  CAS  PubMed  Google Scholar 

  41. Zhao XY, Hu SJ, Li J, Mou Y, Chen BP, Xia Q. Decreased cardiac sarcoplasmic reticulum Ca2+− ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats. J Physiol Biochem. 2006;62:1–8.

    Article  CAS  PubMed  Google Scholar 

  42. Isakova T, Xie H, Yang W, et al. Chronic renal insufficiency cohort (CRIC) study group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305:2432–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–92.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int. 2012;82:737–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partly presented at the annual meeting of American Society of Nephrology Congress, 2013.

We thank Dr. Riko Kitazawa of the division of diagnostic molecular pathology, Kobe University Graduate School of Medicine, for the pathological evaluation and Kayo Tsubota for technical assistance.

This study was partly supported by Chugai Pharmaceutical Co., Ltd and M. H. is an employee of Chugai Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Hideki Fujii, Kentaro Nakai, Yuriko Yonekura, Keiji Kono, Shunsuke Goto, Shinichi Nishi & Masafumi Fukagawa

  2. Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan

    Michinori Hirata

  3. Planning and Development Section, CLEA Japan, Inc, Tokyo, Japan

    Masami Shinohara

  4. Division of Nephrology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan

    Masafumi Fukagawa

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  1. Hideki Fujii
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  2. Kentaro Nakai
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Correspondence to Hideki Fujii.

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Fujii, H., Nakai, K., Yonekura, Y. et al. The Vitamin D Receptor Activator Maxacalcitol Provides Cardioprotective Effects in Diabetes Mellitus. Cardiovasc Drugs Ther 29, 499–507 (2015). https://doi.org/10.1007/s10557-015-6629-y

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