Skip to main content
SpringerLink
Log in

No association between NOS2 and NOS3 polymorphisms and diabetic nephropathy in type 2 diabetics

  • Research Article
  • Published:
Central European Journal of Biology

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Background

Diabetic animal models suggest the involvement of nitric oxide (NO)-producing enzymes in the development of diabetic nephropathy (DN). While early stages of DN are associated with increased intrarenal NO, advanced DN is related to progressive NO deficiency. NO collaborates in reactive nitrogen compounds production, contributing to accelerated oxidative stress. To investigate the impact of genetic polymorphisms of NO-producing enzymes on DN development, we tested 3 polymorphic variants that could affect their function and compared genotype status to an oxidative stress marker.

Methodology

198 Slovenian (Caucasian) type 2 diabetic (T2D) patients, age 34–83, were classified into two groups according to the presence of DN and tested for eNOS Glu298Asp, eNOS 4a/b and iNOS Ser608Leu polymorphisms using PCR and qPCR. Oxidative stress was assessed through serum 8-OHdG level. Results were analyzed using ANOVA, Chi-square test and multivariate logistic regression.

Results

We found no association between the selected polymorphisms and DN. However, we found a significant increase in oxidative stress level in iNOS 608Leu/Leu patients.

Conclusions

We failed to demonstrate the association between the selected eNOS and iNOS genetic polymorphisms and DN. Our results reflect the multifactorial nature of DN in addition to genetic heterogeneity within and between the populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

8-OHdG:

8-hydroxy-2-deoxyguanosine

BMI:

body mass index

CVD:

cardiovascular disease

DF:

diabetic foot

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 (equation):

modification of diet in renal disease (equation)

NO:

nitric oxide

TG:

triglycerides

References

  1. 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 

  2. 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 

  3. Prabhakar S., Role of nitric oxide in diabetic nephropathy, Semin. Nephrol., 2004, 24, 333–344

    Article  PubMed  CAS  Google Scholar 

  4. Rafikov R., Fonseca F.V., Kumar S., Pardo D., Darragh C., Elms S., et al., eNOS activation and NO function: structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity, J. Endocrinol., 2011, 210, 271–284

    Article  PubMed  CAS  Google Scholar 

  5. Yamagishi S., Matsui T., Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy-Friend or foe? Pharmacol. Res., 2011, 64, 187–194

    Article  PubMed  CAS  Google Scholar 

  6. Chatterjee A., Catravas J.D., Endothelial nitric oxide (NO) and its pathophysiologic regulation, Vascul. Pharmacol., 2008, 49, 134–140

    Article  PubMed  CAS  Google Scholar 

  7. Harrison D.G., Chen W., Dikalov S., Li L., Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications, Adv. Pharmacol., 2010, 60, 107–132

    Article  PubMed  CAS  Google Scholar 

  8. Zhao H.J., Wang S., Cheng H., Zhang M., Takahashi T., Fogo A.B., et al., Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice, J. Am. Soc. Nephrol., 2006, 17, 2664–2669

    Article  PubMed  CAS  Google Scholar 

  9. Quaggin S.E., Coffman T.M., Toward a mouse model of diabetic nephropathy: is endothelial nitric oxide synthase the missing link? J. Am. Soc. Nephrol., 2007, 18, 364–366

    Article  PubMed  CAS  Google Scholar 

  10. Mohan S., Reddick R.L., Musi N., Horn D.A., Yan B., Prihoda T.J., et al., Diabetic eNOS knockout mice develop distinct macro- and microvascular complications, Lab. Invest., 2008, 88, 515–528

    Article  PubMed  CAS  Google Scholar 

  11. Nagareddy P.R, Xia Z., McNeill J.H., MacLeod K.M., Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes, Am. J. Physiol. Heart. Circ. Physiol., 2005, 289, 2144–2152

    Article  Google Scholar 

  12. 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

    PubMed  CAS  Google Scholar 

  13. 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

    Google Scholar 

  14. Wang X.L., Sim A.S., Badenhop R.F., McCredie R.M., Wilcken D.E., A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene, Nat. Med., 1996, 2, 41–45

    Article  PubMed  CAS  Google Scholar 

  15. Shlipak M., Diabetic nephropathy, Clinical evidence (Online), 2009, 0606

  16. Szabo C., Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction, Br. J. Pharmacol., 2009, 156, 713–727

    Article  PubMed  CAS  Google Scholar 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. Zintzaras E., Papathanasiou A.A., Stefanidis I., Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: a HuGE review and meta analysis, Genet. Med., 2009, 11, 695–706

    Article  PubMed  CAS  Google Scholar 

  22. Chen Y., Huang H., Zhou J., Doumatey A., Lashley K., Chen G., et al., Polymorphism of the endothelial nitric oxide synthase gene is associated with diabetic retinopathy in a cohort of West Africans, Mol. Vis., 2007, 13, 2142–2147

    PubMed  Google Scholar 

  23. Casas J.P., Bautista L.E., Humphries S.E., Hingorani A.D., Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects, Circulation, 2004, 109, 1359–1365

    Article  PubMed  CAS  Google Scholar 

  24. Joshi M.S., Bauer J.A., Preliminary computational modeling of nitric oxide synthase 3 interactions with caveolin-1: influence of exon 7 Glu298Asp polymorphism, Acta Biochim. Biophys. Sin. (Shanghai), 2008, 40, 47–54

    Article  CAS  Google Scholar 

  25. Tesauro M., Thompson W.C., Rogliani P., Qi L., Chaudhary P.P., Moss J., Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298, Proc. Natl. Acad. Sci. U S A, 2000, 97, 2832–2835

    Article  PubMed  CAS  Google Scholar 

  26. Veldman B.A., Spiering W., Doevendans P.A., Vervoort G., Kroon A.A., de Leeuw P.W. et al., The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide, J. Hypertens., 2002, 20, 2023–2027

    Article  PubMed  CAS  Google Scholar 

  27. Persu A., Stoenoiu M.S., Messiaen T., Davila S., Robino C., El-Khattabi O., et al., Modifier effect of ENOS in autosomal dominant polycystic kidney disease, Hum. Mol. Genet., 2002, 11, 229–241

    Article  PubMed  CAS  Google Scholar 

  28. El-Din Bessa S.S., Hamdy S.M., Impact of Nitric Oxide Synthase Glu298Asp Polymorphism on the Development of End-Stage Renal Disease in Type 2 Diabetic Egyptian Patients, Ren. Fail., 2011, 33, 878–884

    Article  PubMed  Google Scholar 

  29. Thaha M., Pranawa Yogiantoro M., Sutjipto S., Tanimoto M., Gohda T., Tomino Y., Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease, Clin. Neprol., 2008, 70, 144–154

    CAS  Google Scholar 

  30. Cilenšek I., Pilih K., Petrovič D., The 4 A/B polymorphism of the enos gene as a marker for myocardial infarction in type 2 diabetes, Acta Med. Salin., 2009, 38, 13–16

    Google Scholar 

  31. Lembo G., De Luca N., Battagli C., Iovino G., Aretini A., Musicco M., et al., A common variant of endothelial nitric oxide synthase (Glu298Asp) is an independent risk factor for carotid atherosclerosis, Stroke, 2001, 32, 735–740

    Article  PubMed  CAS  Google Scholar 

  32. Johannesen J., Pie A., Pociot F., Kristiansen O.P., Karlsen A.E., Nerup J., et al., Linkage of the human inducible nitric oxide synthase gene to type 1 diabetes, J. Clin. Endocrinol. Metab., 2001, 86, 2792–2796

    Article  PubMed  CAS  Google Scholar 

  33. Lee K.M., Kang D., Park S.K., Berndt S.I., Reding D., Chatterjee N., et al., Nitric oxide synthase gene polymorphisms and prostate cancer risk, Carcinogenesis, 2009, 30, 621–625

    Article  PubMed  CAS  Google Scholar 

  34. Jorge Y.C., Duarte M.C., Silva A.E., Gastric cancer is associated with NOS2 -954G/C polymorphism and environmental factors in a Brazilian population, BMC Gastroenterol., 2010, 10, 64

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Jana Makuc & Danijel Petrovic

Authors
  1. Jana Makuc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danijel Petrovic
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Makuc, J., Petrovic, D. No association between NOS2 and NOS3 polymorphisms and diabetic nephropathy in type 2 diabetics. cent.eur.j.biol. 7, 404–410 (2012). https://doi.org/10.2478/s11535-012-0033-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11535-012-0033-4

Keywords

Search

Navigation