Skip to main content
SpringerLink
Log in

Diminished nitric oxide generation from neutrophils suppresses platelet activation in chronic renal failure

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Chronic renal failure (CRF) is a complex clinical condition associated with accelerated atherosclerosis and thrombosis leading to cardiovascular events. The aim of this study was to investigate in detail the NO pathway in neutrophils obtained from hemodialysis patients and its association with platelet function and oxidative status. Fifteen CRF patients on hemodialysis and fifteen controls were included in this study. Laboratory and experimental evaluations were performed after hemodialysis in CRF patients. We evaluated l-[3H] arginine transport, NO synthase (NOS) activity, amino acid concentration in neutrophils, and expressions of NOS isoforms and p47phox by western blotting. Platelet aggregation was analyzed in the presence or absence of neutrophils. Oxidative status was measured through glutathione peroxidase, catalase activities, protein oxidation, lipid peroxidation, and DNA/RNA oxidation in serum. Basal NOS activity (pmol/106 cells/min) was impaired in CRF patients on hemodialysis (0.33 ± 0.17) compared to controls (0.65 ± 0.12), whereas the expression of NOS isoforms remained unaltered. l-Arginine transport into neutrophils was similar in CRF patients on hemodialysis and controls. In addition, intracellular concentration of l-arginine was increased fourfold in the patient group. Systemic oxidative stress markers were not affected by CRF. On the other hand, NADPH oxidase subunit p47phox in neutrophils was overexpressed in CRF. In the presence of neutrophils, there was a reduction time-dependent in platelet aggregation in both groups with no difference between them. This data suggest that reduced basal generation of NO by neutrophils in CRF patients on hemodialysis occurs independently of l-arginine bioavailability and is able to suppress platelet activation.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. da Silva CD, Brunini TM, Reis PF, Moss MB, Santos SF, Roberts NB, Ellory JC, Mann GE, Mendes-Ribeiro AC (2005) Effects of nutritional status on the l-arginine-nitric oxide pathway in platelets from hemodialysis patients. Kidney Int 68:2173–2179. doi:10.1111/j.1523-1755.2005.00673.x

    Article  PubMed  Google Scholar 

  2. Okamura DM, Himmelfarb J (2009) Tipping the redox balance of oxidative stress in fibrogenic pathways in chronic kidney disease. Pediatr Nephrol 24:2309–2319. doi:10.1007/s00467-009-1199-5

    Article  PubMed  Google Scholar 

  3. Li H, Forstermann U (2013) Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol 13:161–167. doi:10.1016/j.coph.2013.01.006

    Article  PubMed  Google Scholar 

  4. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(829–37):837a–837d. doi:10.1093/eurheartj/ehr304

    Google Scholar 

  5. Brunini TM, Yaqoob MM, Novaes Malagris LE, Ellory JC, Mann GE, Mendes Ribeiro AC (2003) Increased nitric oxide synthesis in uraemic platelets is dependent on l-arginine transport via system y(+)L. Pflügers Arch 445:547–550. doi:10.1007/s00424-002-0978-7

    CAS  PubMed  Google Scholar 

  6. Rodrigues Pereira N, Bandeira Moss M, Assumpcao CR, Cardoso CB, Mann GE, Brunini TM, Mendes-Ribeiro AC (2010) Oxidative stress, l-arginine-nitric oxide and arginase pathways in platelets from adolescents with anorexia nervosa. Blood Cells Mol Dis 44:164–168. doi:10.1016/j.bcmd.2009.12.003

    Article  PubMed  Google Scholar 

  7. Kalyanaraman B (2013) Teaching the basics of redox biology to medical and graduate students: oxidants, antioxidants and disease mechanisms. Redox Biol 1:244–257. doi:10.1016/j.redox.2013.01.014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Moncada S, Higgs EA (2006) Nitric oxide and the vascular endothelium. Handb Exp Pharmacol 176:213–254

    Article  PubMed  Google Scholar 

  9. O’Sullivan S, Medina C, Ledwidge M, Radomski MW, Gilmer JF (2013) Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance: NO and MMP-9 interactions. Biochim Biophys Acta 1843:603–617. doi:10.1016/j.bbamcr.2013.12.006

    Article  Google Scholar 

  10. Lorenc-Koci E, Czarnecka A (2013) Role of nitric oxide in the regulation of motor function: an overview of behavioral, biochemical and histological studies in animal models. Pharmacol Rep 65:1043–1055

    Article  CAS  PubMed  Google Scholar 

  11. Phillipson M, Kubes P (2011) The neutrophil in vascular inflammation. Nat Med 17:1381–1390. doi:10.1038/nm.2514

    Article  CAS  PubMed  Google Scholar 

  12. Wang L, Taneja R, Razavi HM, Law C, Gillis C, Mehta S (2012) Specific role of neutrophil inducible nitric oxide synthase in murine sepsis-induced lung injury in vivo. Shock 37:539–547. doi:10.1097/SHK.0b013e31824dcb5a

    Article  CAS  PubMed  Google Scholar 

  13. Liu G, Place AT, Chen Z, Brovkovych VM, Vogel SM, Muller WA, Skidgel RA, Malik AB, Minshall RD (2012) ICAM-1-activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration. Blood 120:1942–1952. doi:10.1182/blood-2011-12-397430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Glen K, Luu NT, Ross E, Buckley CD, Rainger GE, Egginton S, Nash GB (2012) Modulation of functional responses of endothelial cells linked to angiogenesis and inflammation by shear stress: differential effects of the mechanotransducer CD31. J Cell Physiol 227:2710–2721. doi:10.1002/jcp.23015

    Article  CAS  PubMed  Google Scholar 

  15. Belambri SA, Dang PM, El-Benna J (2014) Evaluation of p47phox phosphorylation in human neutrophils using phospho-specific antibodies. Methods Mol Biol 1124:427–433. doi:10.1007/978-1-62703-845-4_25

    Article  PubMed  Google Scholar 

  16. Muller G, Morawietz H (2009) Nitric oxide, NAD(P)H oxidase, and atherosclerosis. Antioxid Redox Signal 11:1711–1731. doi:10.1089/ARS.2008.2403

    Article  CAS  PubMed  Google Scholar 

  17. Mendes Ribeiro AC, Hanssen H, Kiessling K, Roberts NB, Mann GE, Ellory JC (1997) Transport of l-arginine and the nitric oxide inhibitor NG-monomethyl-l-arginine in human erythrocytes in chronic renal failure. Clin Sci (Lond) 93:57–64

    CAS  Google Scholar 

  18. de Meirelles LR, Resende AC, Matsuura C, Salgado A, Pereira NR, Cascarelli PG, Mendes-Ribeiro AC, Brunini TM (2011) Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure. Clin Exp Pharmacol Physiol 38:705–710. doi:10.1111/j.1440-1681.2011.05580.x

    Article  PubMed  Google Scholar 

  19. Morao I, Periyasamy G, Hillier IH, Joule JA (2006) The role of tetrahydrobiopterin in catalysis by nitric oxide synthase. Chem Commun (Camb). doi:10.1039/b607426j

    Google Scholar 

  20. Chen DD, Shu C, Yang T, Zhou S, Yuan H, Chen AF (2014) Tetrahydrobiopterin regulation of eNOS redox function. Curr Pharm Des 20:3554–3562

    Article  CAS  PubMed  Google Scholar 

  21. Sucher R, Gehwolf P, Oberhuber R, Hermann M, Margreiter C, Werner ER, Obrist P, Schneeberger S, Ollinger R, Margreiter R, Brandacher G (2010) Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury. Kidney Int 77:681–689. doi:10.1038/ki.2010.7

    Article  CAS  PubMed  Google Scholar 

  22. Yamamizu K, Shinozaki K, Ayajiki K, Gemba M, Okamura T (2007) Oral administration of both tetrahydrobiopterin and l-arginine prevents endothelial dysfunction in rats with chronic renal failure. J Cardiovasc Pharmacol 49:131–139. doi:10.1097/FJC.0b013e31802f9923

    Article  CAS  PubMed  Google Scholar 

  23. Bouteldja N, Woodman RJ, Hewitson CL, Domingo E, Barbara JA, Mangoni AA (2013) Methylated arginines and nitric oxide in end-stage renal disease: impact of inflammation, oxidative stress and haemodialysis. Biomarkers 18:357–364. doi:10.3109/1354750X.2013.795608

    Article  CAS  PubMed  Google Scholar 

  24. Jin R, Yu S, Song Z, Zhu X, Wang C, Yan J, Wu F, Nanda A, Granger DN, Li G (2013) Soluble CD40 ligand stimulates CD40-dependent activation of the beta2 integrin Mac-1 and protein kinase C zeda (PKCzeta) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst. PLoS One 8:e64631. doi:10.1371/journal.pone.0064631

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Hossain M, Qadri SM, Liu L (2012) Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. J Inflamm (Lond) 9:28. doi:10.1186/1476-9255-9-28

    Article  CAS  Google Scholar 

  26. Marcus AJ, Safier LB, Ullman HL, Broekman MJ, Islam N, Oglesby TD, Gorman RR, Ward JW (1985) Inhibition of platelet function in thrombosis. Circulation 72:698–701

    Article  CAS  PubMed  Google Scholar 

  27. Tbahriti HF, Kaddous A, Bouchenak M, Mekki K (2014) Effect of different stages of chronic kidney disease and renal replacement therapies on oxidant-antioxidant balance in uremic patients. Biochem Res Int 2013:358985. doi:10.1155/2013/358985

    Google Scholar 

  28. Gunal SY, Ustundag B, Gunal AI (2013) The assessment of oxidative stress on patients with chronic renal failure at different stages and on dialysis patients receiving different hypertensive treatment. Indian J Clin Biochem 28:390–395. doi:10.1007/s12291-013-0316-1

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the Brazilian funding agencies FAPERJ and CNPq.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro, 20551-030, Brazil

    Daniele C. Abrantes, Tatiana M. C. Brunini, Cristiane Matsuura, Wanda Vianna Mury, Carolina R. Corrêa, Monique B. O. Ormonde do Carmo & Antônio Cláudio Mendes-Ribeiro

  2. Nephrology Discipline, University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

    Sérgio F. Santos

  3. Department of Physiological Sciences, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

    Antônio Cláudio Mendes-Ribeiro

Authors
  1. Daniele C. Abrantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatiana M. C. Brunini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristiane Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wanda Vianna Mury
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carolina R. Corrêa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sérgio F. Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Monique B. O. Ormonde do Carmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antônio Cláudio Mendes-Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatiana M. C. Brunini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abrantes, D.C., Brunini, T.M.C., Matsuura, C. et al. Diminished nitric oxide generation from neutrophils suppresses platelet activation in chronic renal failure. Mol Cell Biochem 401, 147–153 (2015). https://doi.org/10.1007/s11010-014-2302-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2302-1

Keywords

Search

Navigation