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H2S donors attenuate diabetic nephropathy in rats: Modulation of oxidant status and polyol pathway

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Abstract

Background

Sulfurous mineral water and its main active ingredient sodium hydrosulfide (NaHS) are major sources of H2S. The present study aimed to explore their protective effect on one of the serious long-term complications of diabetes; diabetic nephropathy.

Methods

Sulfurous mineral water (as drinking water), NaHS (14 μmol/kg/day; ip), and gliclazide (10 mg/kg; po) were administered daily for 6 weeks to streptozotocin (STZ)-diabetic rats.

Results

STZ-induced diabetes was associated with body weight reduction, hyperglycemia, overproduction of glycated hemoglobin, as well as decline in serum insulin, C-peptide, and insulin like growth factor-I. Besides, diabetes impaired kidney functions and imposed oxidative and nitrosative stress as manifested by elevated contents of renal thiobarbituric acid reactive substances and nitric oxide, parallel to reduced glutathione content. These deleterious effects were antagonized by sulfurous water and to a better extent by NaHS. Activities of myeloperoxidase and sorbitol dehydrogenase were not altered by STZ or any of the treatments. However, STZ-induced diabetes was accompanied by an increment of aldose reductase which was only mitigated by gliclazide and NaHS. Histopathological examination of kidney sections corroborated the biochemical findings.

Conclusion

This study suggests a novel therapeutic approach for diabetic nephropathy using H2S donors.

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Abbreviations

AR:

aldose reductase

HbA1C %:

glycated hemoglobin

IGF-I:

insulin like growth factor-I

MPO:

myeloperoxidase

GSH:

reduced glutathione

NaHS:

sodium hydrosulfide

SD:

sorbitol dehydrogenase

STZ:

streptozotocin

TBARs:

thiobarbituric acid reactive substance content

NOx:

total nitrate/nitrite content

References

  1. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341(15):1127–33.

    Article  CAS  PubMed  Google Scholar 

  2. Hakim FA, Pflueger A. Role of oxidative stress in diabetic kidney disease. Med Sci Monit 2010;16(2):RA37–48.

    Google Scholar 

  3. Itagaki I, Shimizu K, Kamanaka Y, Ebata K, Kikkawa R, Haneda M, et al. The effect of an aldose reductase inhibitor (epalrestat) on diabetic nephropathy in rats. Diabetes Res Clin Pract 1994;25(3):147–54.

    Article  CAS  PubMed  Google Scholar 

  4. Wang R. Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Signal 2010;12(9):1061–4.

    Article  CAS  PubMed  Google Scholar 

  5. Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids 2011;41(1):113–21.

    Article  CAS  PubMed  Google Scholar 

  6. Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 2007;6(11):917–35.

    Article  CAS  PubMed  Google Scholar 

  7. Rinaldi L, Gobbi G, Pambianco M, Micheloni C, Mirandola P, Vitale M. Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3. Lab Invest 2006;86(4):391–7.

    Article  CAS  PubMed  Google Scholar 

  8. Lowicka E, Beltowski J. Hydrogen sulfide (H2S) – the third gas of interest for pharmacologists. Pharmacol Rep 2007;59(1):4–24.

    CAS  PubMed  Google Scholar 

  9. Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M, Cirino G. Biosynthesis of H2S is impaired in non-obese diabetic (nod) mice. Br J Pharmacol 2008;155(5):673–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jain SK, Bull R, Rains JL, Bass PF, Levine SN, Reddy S, et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal 2010;12(11):1333–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gupta AK, Nicol K. The use of sulfur in dermatology. J Drugs Dermatol 2004;3(4):427–31.

    PubMed  Google Scholar 

  12. Sukenik S, Flusser D, Abu-Shakra M. The role of spa therapy in various rheumatic diseases. Rheum Dis Clin North Am 1999;25(4):883–97.

    Article  CAS  PubMed  Google Scholar 

  13. Costantino M, Giuberti G, Caraglia M, Lombardi A, Misso G, Abbruzzese A, et al. Possible antioxidant role of spa therapy with chlorine–sulphur–bicarbonate mineral water. Amino Acids 2009;36(2):161–5.

    Article  CAS  PubMed  Google Scholar 

  14. Casetta I, Govoni V, Granieri E. Oxidative stress, antioxidants and neurodegenerative diseases. Curr Pharm Des 2005;11(16):2033–52.

    Article  CAS  PubMed  Google Scholar 

  15. Saito M, Kinoshita Y, Satoh I, Shinbori C, Kono T, Hanada T, et al. N-hexacosanol ameliorates streptozotocin-induced diabetic rat nephropathy. Eur J Pharmacol 2006;544(1–3):132–7.

    Article  CAS  PubMed  Google Scholar 

  16. Matthaei S, Horuk R, Olefsky JM. Blood–brain glucose transfer in diabetes mellitus. Decreased number of glucose transporters at blood–brain barrier. Diabetes 1986;35(10):1181–4.

    Article  CAS  PubMed  Google Scholar 

  17. Benedetti S, Benvenuti F, Nappi G, Fortunati NA, Marino L, Aureli T, et al. Antioxidative effects of sulfurous mineral water: protection against lipid and protein oxidation. Eur J Clin Nutr 2009;63(1):106–12.

    Article  CAS  PubMed  Google Scholar 

  18. Geng B, Chang L, Pan C, Qi Y, Zhao J, Pang Y, et al. Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 2004;318(3):756–63.

    Article  CAS  PubMed  Google Scholar 

  19. Attia HN, Al-Rasheed NM, Maklad YA, Ahmed AA, Kenawy SA. Protective effects of combined therapy of gliclazide with curcumin in experimental diabetic neuropathy in rats. Behav Pharmacol 2012;23(2):153–61.

    Article  CAS  PubMed  Google Scholar 

  20. Warenycia MW, Smith KA, Blashko CS, Kombian SB, Reiffenstein RJ. Monoamine oxidase inhibition as a sequel of hydrogen sulfide intoxication: increases in brain catecholamine and 5-hydroxytryptamine levels. Arch Toxicol 1989;63(2):131–6.

    Article  CAS  PubMed  Google Scholar 

  21. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978;86(1):271–8.

    CAS  PubMed  Google Scholar 

  22. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882–8.

    CAS  PubMed  Google Scholar 

  23. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001;5(1):62–71.

    CAS  PubMed  Google Scholar 

  24. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 1982;78(3):206–9.

    CAS  PubMed  Google Scholar 

  25. Hoffman PL, Wermuth B, von Wartburg JP. Human brain aldehyde reductases: relationship to succinic semialdehyde reductase and aldose reductase. J Neurochem 1980;35(2):354–66.

    Article  CAS  PubMed  Google Scholar 

  26. Chauncey B, Leite MV, Goldstein L. Renal sorbitol accumulation and associated enzyme activities in diabetes. Enzyme 1988;39(4):231–4.

    Article  CAS  PubMed  Google Scholar 

  27. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193(1):265–75.

    CAS  PubMed  Google Scholar 

  28. El-Seweidy MM, Sadik NA, Shaker OG. Role of sulfurous mineral water and sodium hydrosulfide as potent inhibitors of fibrosis in the heart of diabetic rats. Arch Biochem Biophys 2011;506(1):48–57.

    Article  CAS  PubMed  Google Scholar 

  29. Xue R, Hao DD, Sun JP, Li WW, Zhao MM, Li XH, et al. Hydrogen sulfide treatment promotes glucose uptake by increasing insulin receptor sensitivity and ameliorates kidney lesions in type 2 diabetes. Antioxid Redox Signal 2013;19(1):5–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 1978;253(8):2769–76.

    CAS  PubMed  Google Scholar 

  31. Kook S, Kim GH, Choi K. The antidiabetic effect of onion and garlic in experimental diabetic rats: meta-analysis. J Med Food 2009;12(3):552–60.

    Article  CAS  PubMed  Google Scholar 

  32. Klimek M, Wang S, Ogunkanmi A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. P T 2009;34(6):313–27.

    PubMed  PubMed Central  Google Scholar 

  33. Morsy MD, Hassan WN, Zalat SI. Improvement of renal oxidative stress markers after ozone administration in diabetic nephropathy in rats. Diabetol Metab Syndr 2010;2(1):29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Xu Y, Osborne BW, Stanton RC. Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex. Am J Physiol Renal Physiol 2005;289(5): F1040–47.

    Article  CAS  PubMed  Google Scholar 

  35. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008;57(6):1446–54.

    Article  CAS  PubMed  Google Scholar 

  36. Hamilton KL, Butt AG. The molecular basis of renal tubular transport disorders. Comp Biochem Physiol A: Mol Integr Physiol 2000;126(3):305–21.

    Article  CAS  Google Scholar 

  37. Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol 2003;14(8 Suppl. 3):S254–8.

    Article  CAS  PubMed  Google Scholar 

  38. Karachalias N, Babaei-Jadidi R, Ahmed N, Thornalley PJ. Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats. Biochem Soc Trans 2003;31(Pt 6):1423–5.

    Article  CAS  PubMed  Google Scholar 

  39. Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB. Role of high glucose-induced nuclear factor-kappab activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol 2002;13(4):894–902.

    CAS  PubMed  Google Scholar 

  40. Al-Rasheed NM, Willars GB, Brunskill NJ. C-peptide signals via Galpha i to protect against TNF-alpha-mediated apoptosis of opossum kidney proximal tubular cells. J Am Soc Nephrol 2006;17(4):986–95.

    Article  CAS  PubMed  Google Scholar 

  41. Caraglia M, Beninati S, Giuberti G, D’Alessandro AM, Lentini A, Abbruzzese A, et al. Alternative therapy of earth elements increases the chondroprotective effects of chondroitin sulfate in mice. Exp Mol Med 2005;37(5):476–81.

    Article  CAS  PubMed  Google Scholar 

  42. Tripatara P, Patel NS, Brancaleone V, Renshaw D, Rocha J, Sepodes B, et al. Characterisation of cystathionine gamma-lyase/hydrogen sulphide pathway in ischaemia/reperfusion injury of the mouse kidney: an in vivo study. Eur J Pharmacol 2009;606(1–3):205–9.

    Article  CAS  PubMed  Google Scholar 

  43. Jung KJ, Jang HS, Kim JI, Han SJ, Park JW, Park KM. Involvement of hydrogen sulfide and homocysteine transsulfuration pathway in the progression of kidney fibrosis after ureteral obstruction. Biochim Biophys Acta 2013;1832(12): 1989–97.

    Article  CAS  PubMed  Google Scholar 

  44. Barbagallo M, Dominguez LJ, Galioto A, Ferlisi A, Cani C, Malfa L, et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med 2003;24(1–3):39–52.

    Article  CAS  PubMed  Google Scholar 

  45. Liu CT, Wong PL, Lii CK, Hse H, Sheen LY. Antidiabetic effect of garlic oil but not diallyl disulfide in rats with streptozotocin-induced diabetes. Food Chem Toxicol 2006;44(8):1377–84.

    Article  CAS  PubMed  Google Scholar 

  46. Nandhini TA, Anuradha CV. Inhibition of lipid peroxidation, protein glycation and elevation of membrane ion pump activity by taurine in RBC exposed to high glucose. Clin Chim Acta 2003;336(1–2):129–35.

    Article  CAS  PubMed  Google Scholar 

  47. Dominguez C, Ruiz E, Gussinye M, Carrascosa A. Oxidative stress at onset and in early stages of type 1 diabetes in children and adolescents. Diabetes Care 1998;21(10):1736–42.

    Article  CAS  PubMed  Google Scholar 

  48. Drel VR, Pacher P, Stevens MJ, Obrosova IG. Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. Free Radic Biol Med 2006;40(8):1454–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sung JK, Koh JH, Lee MY, Kim BH, Nam SM, Kim JH, et al. Aldose reductase inhibitor ameliorates renal vascular endothelial growth factor expression in streptozotocin-induced diabetic rats. Yonsei Med J 2010;51(3): 385–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kicic E, Palmer TN. Is sorbitol dehydrogenase gene expression affected by streptozotocin-diabetes in the rat? Biochim Biophys Acta 1994;1226(2): 213–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Marwa M. Safar & Rania M. Abdelsalam

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  1. Marwa M. Safar
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Correspondence to Marwa M. Safar.

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Safar, M.M., Abdelsalam, R.M. H2S donors attenuate diabetic nephropathy in rats: Modulation of oxidant status and polyol pathway. Pharmacol. Rep 67, 17–23 (2015). https://doi.org/10.1016/j.pharep.2014.08.001

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  • DOI: https://doi.org/10.1016/j.pharep.2014.08.001

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