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Vitamin D improves diabetic nephropathy in rats by inhibiting renin and relieving oxidative stress

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Abstract

Background

It is well established that the activation of the renin–angiotensin system (RAS) and the oxidative stress caused by hyperglycemia are major mediators of the development and progression of diabetic nephropathy (DN). Vitamin D may be important in maintaining podocyte health, preventing epithelial-to-mesenchymal transformation, and suppressing renin gene expression and inflammation, but its mechanism requires clarification. This study evaluated the specific mechanism of vitamin D to DN improvement.

Methods

We induced a rat model of diabetes with an intraperitoneal injection of streptozotocin (60 mg/kg). The streptozotocin-induced diabetic rats were fed normal chow for about 2 months to induce the DN model. The DN rats were then treated with irbesartan and/or calcitriol, administered intragastrically about 1 month.

Results

The rats displayed the early characteristics of DN, including increased microalbuminuria, obvious hypertrophic kidney, and a markedly increased kidney weight/bodyweight ratio. Vitamin D inhibited the compensatory increase in renin expression. Malondialdehyde, which reflects oxidative stress levels, was elevated in the DN group rats and their antioxidant capacity was significantly reduced. The irbesartan and calcitriol interventions markedly improved the renal pathology and pathophysiological changes. Irbesartan combined with vitamin D (calcitriol) more effectively ameliorated DN than irbesartan alone.

Conclusions

Vitamin D combined with angiotensin II type 1 receptor blockers exerts a synergistic effect on the treatment of DN, not only by inhibiting renin but also by reducing oxidative stress and increasing the renal antioxidant capacity.

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References

  1. Ritz E, Rychlik I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 34:795–808

    Article  CAS  PubMed  Google Scholar 

  2. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML et al (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–176

    Article  PubMed  Google Scholar 

  3. Remuzzi G, Schieppati A, Ruggenenti P (2002) Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med 346:1145–1151

    Article  PubMed  Google Scholar 

  4. Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH (2000) Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 57:601–606

    Article  CAS  PubMed  Google Scholar 

  5. Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J (2007) Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med 24:486–493

    Article  CAS  PubMed  Google Scholar 

  6. Forbes JM, Coughlan MT, Cooper ME (2008) Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57:1446–1454

    Article  CAS  PubMed  Google Scholar 

  7. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S et al (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878

    Article  CAS  PubMed  Google Scholar 

  8. Li YC, Kong J, Wei M, Chen ZF, Liu SQ et al (2002) 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yuan W, Pan W, Kong J, Zheng W, Szeto FL et al (2007) 1,25-Dihydroxyvitamin D3 Suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 282:29821–29830

    Article  CAS  PubMed  Google Scholar 

  10. Li YC (2011) Podocytes as target of vitamin D. Curr Diabetes Rev 7:35–40

    Article  CAS  PubMed  Google Scholar 

  11. Izquierdo MJ, Cavia M, Muñiz P, de Francisco AL, Arias M et al (2012) Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients. BMC Nephrol 13:159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Diaz VA, Mainous AG, Carek PJ, Wessell AM, Everett CJ (2009) The association of vitamin D deficiency and insufficiency with diabetic nephropathy: implications for health disparities. J Am Board Fam Med 22:521–527

    Article  PubMed  Google Scholar 

  13. Zhou QX, Liu F, Zhang JS, Lu JG, Gu ZL et al (2013) Effects of triterpenic acid from Prunella vulgaris L. on glycemia and pancreas in rat model of streptozotozin diabetes. Chin Med J (Engl) 126:1647–1653

    CAS  Google Scholar 

  14. Zhang Z, Sun L, Wang Y, Ning G, Minto AW et al (2008) Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 73:163–171

    Article  CAS  PubMed  Google Scholar 

  15. Montilla P, Barcos M, Munoz MC, Bujalance I, Munoz-Castaneda JR et al (2005) Red wine prevents brain oxidative stress and nephropathy in streptozotocin-induced diabetic rats. J Biochem Mol Biol 38:539–544

    Article  CAS  PubMed  Google Scholar 

  16. Raza H, Prabu SK, John A, Avadhani NG (2011) Impaired mitochondrial respiratory functions and oxidative stress in streptozotocin-induced diabetic rats. Int J Mol Sci 12:3133–3147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Z, Zhang Y, Ning G, Deb DK, Kong J et al (2008) Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci USA 105:15896–15901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang Y, Deb DK, Kong J, Ning G, Wang Y et al (2009) Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist. Am J Physiol Renal Physiol 297:F791–F801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ohara I, Tanimoto M, Gohda T, Yamazaki T, Hagiwara S et al (2011) Effect of combination therapy with angiotensin receptor blocker and 1,25-dihydroxyvitamin D(3) in type 2 diabetic nephropathy in KK-A(y)/Ta mice. Nephron Exp Nephrol 117:e124–e132

    Article  CAS  PubMed  Google Scholar 

  20. Cetinkalp S, Delen Y, Karadeniz M, Yüce G, Yilmaz C (2009) The effect of 1alpha, 25(OH)2D3 vitamin over oxidative stress and biochemical parameters in rats where Type 1 diabetes is formed by streptozotocin. J Diabetes Complications 23:401–408

    Article  PubMed  Google Scholar 

  21. Singh DK, Winocour P, Farrington K (2011) Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 7:176–184

    Article  CAS  PubMed  Google Scholar 

  22. Takayanagi R, Inoguchi T, Ohnaka K (2011) Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus. J Clin Biochem Nutr 48:72–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fujita H, Fujishima H, Morii T, Sakamoto T, Komatsu K et al (2012) Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice. Hypertens Res 35:213–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee WC, Chen HC, Wang CY, Lin PY, Ou TT et al (2010) Cilostazol ameliorates nephropathy in type 1 diabetic rats involving improvement in oxidative stress and regulation of TGF-Beta and NF-kappaB. Biosci Biotechnol Biochem 74:1355–1361

    Article  CAS  PubMed  Google Scholar 

  26. Hamden K, Carreau S, Jamoussi K, Miladi S, Lajmi S et al (2009) 1Alpha,25 dihydroxyvitamin D3: therapeutic and preventive effects against oxidative stress, hepatic, pancreatic and renal injury in alloxan-induced diabetes in rats. J Nutr Sci Vitaminol (Tokyo) 55:215–222

    Article  CAS  Google Scholar 

  27. Del Pino-Montes J, Benito GE, Fernández-Salazar MP, Coveñas R, Calvo JJ et al (2004) Calcitriol improves streptozotocin-induced diabetes and recovers bone mineral density in diabetic rats. Calcif Tissue Int 75:526–532

    Article  CAS  PubMed  Google Scholar 

  28. Baeke F, Van Belle TL, Takiishi T, Ding L, Korf H et al (2012) Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes. Diabetologia 55:2723–2732

    Article  CAS  PubMed  Google Scholar 

  29. Skyler JS (2013) Primary and secondary prevention of Type 1 diabetes. Diabet Med 30:161–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Deb DK, Sun T, Wong KE, Zhang Z, Ning G et al (2010) Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. Kidney Int 77:1000–1009

    Article  CAS  PubMed  Google Scholar 

  31. Esteghamati A, Aryan Z, Esteghamati A, Nakhjavani M (2014) Differences in vitamin D concentration between metabolically healthy and unhealthy obese adults: Associations with inflammatory and cardiometabolic markers in 4391 subjects. Diabetes Metab 40:347–355

    CAS  PubMed  Google Scholar 

  32. Raab J, Giannopoulou EZ, Schneider S, Warncke K, Krasmann M et al (2014) Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression. Diabetologia 57:902–908

    Article  CAS  PubMed  Google Scholar 

  33. Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Yakout SM et al (2014) Lower vitamin D status is more common among Saudi adults with diabetes mellitus type 1 than in non-diabetics. BMC Public Health 14:153

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the Social and Science Foundation of Changzhou, Jiangsu Province, China (CS20092021).

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Author notes

    Authors and Affiliations

    1. Department of Endocrinology, Wuhan Third Hospital, Wuhan University, 430062, Wuhan, China

      X. Deng

    2. Department of Endocrinology, Changzhou No. 2 People’s Hospital, Nanjing Medical University, 213003, Changzhou, China

      J. Cheng & M. Shen

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    1. X. Deng
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    2. J. Cheng
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    Correspondence to X. Deng.

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    There is no conflict of interest to be reported for this manuscript.

    Ethical approval

    All procedures performed in studies involving animals were approved by the Animal Ethics Committee of Changzhou Second People’s Hospital affiliated to Nanjing Medical University and carried out in accordance with the Guideline on the Humane Treatment of Laboratory Animals (China).

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    Additional information

    X. Deng and J. Cheng contributed equally to this work.

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    Deng, X., Cheng, J. & Shen, M. Vitamin D improves diabetic nephropathy in rats by inhibiting renin and relieving oxidative stress. J Endocrinol Invest 39, 657–666 (2016). https://doi.org/10.1007/s40618-015-0414-4

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    • DOI: https://doi.org/10.1007/s40618-015-0414-4

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