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Diabetic nephropathy in type 2 diabetes: MPO T-764C genotype is associated with oxidative stress

  • Research Article
  • Published:
Central European Journal of Biology

Abstract

Background

Oxidative stress is a single mechanism relating all major pathways responsible for diabetic damage and plays an important role in diabetes development, progression and related vascular complications. To investigate the impact of oxidative stress related gene polymorphisms on development of diabetic nephropathy (DN), we tested 7 polymorphic variants that could hypothetically affect the ability of the antioxidant defense system and thus accelerate oxidative stress.

Methodology

197 Slovenian (Caucasian) type 2 diabetic (T2D) patients, age 34–83, classified into two groups according to the presence of DN, were tested for SOD2 Val16Ala (rs4880), p22 phox C242T (rs4673), CAT C-262T (rs1001179), MPO T-764C (rs2243828), GSTP1 Ile105Val (rs1695), GSTT1 and GSTM1 deletion polymorphisms using PCR, RFLP and qPCR. Oxidative stress was assessed through serum 8-hydroxy-2-deoxyguanosine (8-OHdG) level. Results were analyzed using ANOVA, Chi-square test and multivariate logistic regression.

Results and Conclusions

Despite the commonly recognized link between oxidative stress and diabetes and its complications we found no association between the selected polymorphisms and DN. However, we confirmed an association between oxidative stress level and MPO T-764C genotype, which was tested in relation to DN for the first time.

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Abbreviations

8-OHdG:

8-hydroxy-2-deoxyguanosine

BMI:

body mass index

CVD:

cardiovascular disease

DF:

diabetic foot

DBP:

diastolic blood pressure

DN:

diabetic nephropathy

DNeur:

diabetic neuropathy

DR:

diabetic retinopathy

eGFR:

estimated glomerular filtration rate

Hb:

haemoglobin

HbA1c:

haemoglobin A1c, glycated haemoglobin

HDL:

high-density lipoprotein

LDL:

low-density lipoprotein

MDRD:

modification of diet in renal disease

NO:

nitric oxide

SPB:

systolic blood pressure

TG:

triglycerides

SNP:

single-nucleotide polymorphism

References

  1. Shlipak M., Diabetic nephropathy, Clin Evid (Online), 2009, 0606

  2. Conway B.R., Maxwell A.P., Genetics of diabetic nephropathy: are there clues to the understanding of common kidney diseases? Nephron. Clin. Pract., 2009, 112, 213–221

    Article  Google Scholar 

  3. Carpena M.P., Rados D.V., Sortica D.A., deSouza B.M., Reis A.F., Canani L.H., et al., Genetics of diabetic nephropathy, Arq. Bras. Endocrinol. Metab., 2010, 54, 254–261

    Article  Google Scholar 

  4. Gnudi L., Goldsmith D., Renin angiotensin aldosterone system (RAAS) inhibitors in the prevention of early renal disease in diabetes, F1000 Med Rep, 2010, 2, 18

    PubMed  Google Scholar 

  5. Baynes J W., Role of oxidative stress in development of complications in diabetes, Diabetes, 1991, 40, 405–412

    Article  PubMed  CAS  Google Scholar 

  6. Ceriello A., dello Russo P., Amstad P., Cerutti P., High glucose induces antioxidant enzymes in human endothelial cells in culture, Evidence linking hyperglycemia and oxidative stress, Diabetes, 1996, 45, 471–477

    CAS  Google Scholar 

  7. Nishikawa T., Edelstein D., Brownlee M., The missing link: a single unifying mechanism for diabetic complications, Kidney Int. Suppl., 2000, 77, 26–30

    Article  Google Scholar 

  8. Brownlee M., The Pathobiology of Diabetic Complications, A unifying Mechanism, Diabetes, 2005, 54, 1615–1625

    CAS  Google Scholar 

  9. Forbes J., Coughlan M.T., Cooper M.E., Oxidative stress as a major culprit in kidney disease in diabetes, Diabetes, 2008, 57, 1446–1454

    Article  PubMed  CAS  Google Scholar 

  10. Kim J., We, Y., Sowers J.R., Role of mitochondrial dysfunction in insulin resistance, Circ. Res., 2008, 102, 401–414

    Article  PubMed  CAS  Google Scholar 

  11. Gao L., Mann G.E., Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signaling, Cardiovasc. Res., 2009, 82, 19–20

    Article  Google Scholar 

  12. Yamagishi S., Matsui T, Advanced glycation end products, oxidative stress and diabetic nephropathy, Oxid. Med. Cell. Longev., 2010, 32, 101–108

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Wink D.A., Miranda K.M., Espey M.G., Cytotoxicity related to oxidative and nitrosative stress by nitric oxide, Exp. Biol. Med., 2001, 226, 621–623

    CAS  Google Scholar 

  15. Valavanidis A., Vlachogianni T., Fiotakis C., 8-hydroxy-2′-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis, J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev., 2009, 27, 120–139

    Article  PubMed  CAS  Google Scholar 

  16. Halliwell B., Why and how should we measure oxidative DNA damage in nutritional studies? How far have we come? Am. J. Clin. Nutr., 2000, 72, 1082–1087

    PubMed  CAS  Google Scholar 

  17. Al-Aubaidy H.A., Jelinek H.F., 8-Hydroxy-2-deoxyguanosine identifies oxidative DNA damage in a rural prediabetes cohort, Redox Rep., 2010, 15, 155–160

    Article  PubMed  CAS  Google Scholar 

  18. Dincer Y., Sekercioglu N., Pekpak M., Gunes K.N., Akcay T., Assessment of DNA oxidation and antioxidant activity in hypertensive patients with chronic kidney disease, Ren. Fail., 2008, 30, 1006–1011

    Article  PubMed  CAS  Google Scholar 

  19. Pan H.Z., Zhang L., Guo M.Y., Sui H., Li H., Wu W.H., et al., The oxidative stress status in diabetes mellitus and diabetic nephropathy, Acta Diabetol., 2010, 47, 71–76

    Article  PubMed  CAS  Google Scholar 

  20. Zelko I.N., Mariani T.J., Folz R.J., Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and ECSOD (SOD3) gene structures, evolution, and expression, Free Radic. Biol. Med., 2002, 33, 337–349

    Article  PubMed  CAS  Google Scholar 

  21. Goyal M.M., Basak A., Human catalase: looking for complete identity, Protein Cell, 2010, 1, 888–897

    Article  PubMed  CAS  Google Scholar 

  22. Josephy, P.D., Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology, Hum. Genomics Proteomics, 2010, 876940

  23. Loria V., Dato I., Graziani F., Biasucci L.M., Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes, Mediators Inflamm., 2008, 135625

  24. Schindhelm R.K., van der Zwan L.P., Teerlink T., Scheffer P.G. Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification? Clin. Chem., 2009, 55, 1462–1470

    Article  PubMed  CAS  Google Scholar 

  25. Paravicini T.M., Touyz R.M., NADPH oxidases, reactive oxygen species and hypertension, Diab. Care, 2008, 31, 170–180

    Article  Google Scholar 

  26. Makuc J., Petrovič D., A Review Of Oxidative Stress Related Genes And New Antioxidant Therapy In Diabetic Nephropathy, Cardiovasc. Hematol. Agents Med. Chem., 2012, 9, 253–261

    Article  Google Scholar 

  27. World Health Organization, Part 1: Diagnosis and Classification of Diabetes Mellitus: Report of a WHO consultation, In: Alwan A., King H., (Eds.), Definition, diagnosis and classification of diabetes mellitus and its complications, World Health Department of Noncommunicable Disease Surveillance, Geneva, 1999

  28. Makuc J., Petrovic D., No association between NOS2 and NOS3 polymorphisms and diabetic nephropathy in type 2 diabetics, Centr. Eur. J. Biol., 2012, 7, 404–410

    Article  CAS  Google Scholar 

  29. Sutton A., Khoury H., Prip-Buus C., Cepanec C., Pessayre D., Degoul F., The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria, Pharmacogenetics, 2003, 13, 145–157

    Article  PubMed  CAS  Google Scholar 

  30. Flekac M., Skrha J., Hilgertova J., Lacinova Z., Jarolimkova M., Gene polymorphisms of superoxide dismutases and catalase in diabetes mellitus, BMC Med. Genet., 2008, 9, 30

    Article  PubMed  Google Scholar 

  31. Chistyakov D.A., Savostánov K.V., Zotova E.V., Nosikov V.V., Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus, BMC Med. Genet., 2001, 2, 4

    Article  PubMed  CAS  Google Scholar 

  32. Nomiyama T., Tanaka Y., Piap L., Nagasaka K., Sakai K., Ogihara T., et al., The polymorphism of manganese superoxide dismutase is associated with diabetic nephropathy in Japanese type 2 diabetic patients, J. Hum. Gen., 2003, 48, 138–141

    CAS  Google Scholar 

  33. Lee S.J., Choi M.G., Kim D.S., Kim T. W., Manganese superoxide dismutase gene polymorphism (V16A) is associated with stages of albuminuria in Korean type 2 diabetic patients, Metabol., 2006, 55, 1–7

    Article  CAS  Google Scholar 

  34. Globocnik Petrovic M., Cilensek I., Petrovic D. Manganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patients, Dis. Markers, 2008, 24, 59–64

    Google Scholar 

  35. Hovnik T., Dolžan V., Ursic Bratina N., Trebusak Podkrajsek K., Battelino T., Genetic polymorphisms in genes encoding antioxidant enzymes are associated with diabetic retinopathy in type 1 diabetes, Diab. Care, 2009, 32, 2258–2262

    Article  CAS  Google Scholar 

  36. Möllstein A., Jorsal A., Lajer M., Vionnet N., The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in typle 1 diabetes, Diabetologia, 2009, 52, 2590–2593

    Article  Google Scholar 

  37. Tian C., Fang S., Du X., Jia C., Association of the C47T polymorphism in SOD2 with diabetes mellitus and diabetic microvascular complications: a meta analysis, Diabetologia, 2011, 54, 803–811

    Article  PubMed  CAS  Google Scholar 

  38. Kedziora-Kornatowska K.Z., Luciak M., Blaszczyk J., Pawlak W., Lipid peroxidation and activities of antioxidant enzymes in erythrocytes of patients with non-insulin dependent diabetes with or without diabetic nephropathy, Nephrol. Dial. Transplant., 1998, 13, 2829–2832

    Article  PubMed  CAS  Google Scholar 

  39. Hodgkinson A.D., Bartlett T., Oates P.J., Millward B.A., The response of antioxidant genes to hyperglycaemia is abnormal in patients with type 1 diabetes and diabetic nephropathy, Diabetes, 2003, 52, 846–851

    Article  PubMed  CAS  Google Scholar 

  40. Chistiakov D.A., Zotova E.V., Savostánov K.V., Bursa T.R., Galeev I.V., Strokov I.A., et al., The 262T>C promoter polymorphism of the catalase gene is associated with diabetic neuropathy in type 1 diabetic Russian patients, Diab. Metabol., 2006, 32, 63–68

    Article  CAS  Google Scholar 

  41. Gorin Y., Block K., Hernandez J., Bhandari B., Wagner B., Brnes J.L., et al., Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney, J. Biol. Chem., 2005, 280, 39616–39626

    Article  PubMed  CAS  Google Scholar 

  42. Hodgkinson A.D., Millward B.A., Demaine A.G., Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes, Diab. Care, 2003, 26, 3111–3115

    Article  CAS  Google Scholar 

  43. Matsunaga-Irie S., Maruyama T., Yamamoto Y., Motohashi Y., Hirose H., Shimada A., et al., Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients, Diab. Care, 2004, 27, 303–307

    Article  CAS  Google Scholar 

  44. Ewens K.G., George R.A., Sharma K., Zidayeh F.N., Speilman R.S., Assessment of 115 candidate genes for diabetic nephropathy by transmission/disequilibrium test, Diabetes, 2005, 54, 3305–3318

    Article  PubMed  CAS  Google Scholar 

  45. Inoue N., Kawashima S., Kanazawa K., Yamada S., Akita H., Yokoyama M., Polymorphism of the NADH/NADPH Oxidase p22 phox Gene in Patients With Coronary Artery Disease, Circulation, 1998, 97, 135–137

    Article  PubMed  CAS  Google Scholar 

  46. Piedrafita F.J., Molander R.B., Vansant G., Orlova E.A., Pfahl M., Reynolds W.F., An Alu Element in the Myeloperoxidase Promoter Contains a Composite SP1-Thyroid Hormone-Retinoic Acid Response Element, J. Biol. Chem., 1996, 271, 14412–14420

    Article  PubMed  CAS  Google Scholar 

  47. Ambrosone C.B., Ahn J., Singh K.K., Rezaishiraz H., Furberg H., Sweeney C., et al., Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer, Cancer Res., 2005, 65, 1105–1111

    PubMed  CAS  Google Scholar 

  48. Gu F., Qureshi A.A., Kraft P., Guo Q., Hunter D.J., Han J., Polymorphisms in genes involved in DNA repair, cell growth, oxidative stress and inflammatory response, and melanoma risk, Br. J. Dermatol., 2009, 161, 209–212

    Article  PubMed  CAS  Google Scholar 

  49. He C., Tamimi R.M., Hankinson S.E., Hunter D.J., Han J., A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk, Breast Cancer Res. Treat., 2009, 113, 585–594

    Article  PubMed  CAS  Google Scholar 

  50. Yang Y., Kao M.T., Chang C.C., Chung S.Y., Chen C.M., Tsa, J.J., et al., Glutathione S-transferase T1 deletion is a risk factor for developing end-stage renal disease in diabetic patients, Int. J. Mol. Med., 2004, 14, 855–859

    PubMed  CAS  Google Scholar 

  51. Doney A.S.F., Lee S., Leese G.P., Morris A.D., Palmer C.A.N., Increased cardiovascular morbidity and mortality in type 2 diabetes is associated with the gluthatione S-transferase theta-Null genotype: a Go-DARTS Study, Circulation, 2005, 111, 2927–2934

    Article  PubMed  CAS  Google Scholar 

  52. Datta S.K., Kumar V., Ahmed R.S., Tripathi A.K., Kalra O.P., Banerjee B.D. Effect of GSTM1 and GSTT1 double deletions in the development of oxidative stress in diabetic nephropathy patients, Indian J. Biochem. Biophys., 2010, 47, 100–103

    PubMed  CAS  Google Scholar 

  53. Fujita H., Narita T., Meguro H., Shimotomai T., Kitazato H., Kagaya E., et al., No association of gluthatione S-transferase M1 gene polymorphism with diabetic nephropathy in Japanese type 2 diabetic patients, Ren. Fail., 2000, 22, 479–486

    Article  PubMed  CAS  Google Scholar 

  54. Tiwari A.K., Prasad P., Thelma B.K., Prasanna Kumar K.M., Ammini A.C., Gupta A., et al., Oxidative stress pathway genes and chronic renal insufficiency in Asian Indians with type 2 diabetes, J. Diab. Comp., 2009, 23, 102–111

    Article  Google Scholar 

  55. Bid H.K., Konwar R., Saxena M., Chaudhari P., Agrawal C.G., Banerjee M. Association of gluthationeS-transferase (GSTM1, T1 and P1) gene polymorphisms with type 2 diabetes mellitus in north Indian population, JPGM, 2010, 56, 176–181

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia

    Jana Makuc & Danijel Petrovic

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  1. Jana Makuc
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  2. Danijel Petrovic
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Correspondence to Danijel Petrovic.

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Makuc, J., Petrovic, D. Diabetic nephropathy in type 2 diabetes: MPO T-764C genotype is associated with oxidative stress. cent.eur.j.biol. 7, 964–972 (2012). https://doi.org/10.2478/s11535-012-0105-5

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