Pediatric Nephrology

, Volume 24, Issue 5, pp 1033–1038 | Cite as

Increased nitric oxide production by T- and B-cells in idiopathic nephrotic syndrome

  • Anna Iharada
  • Kazunari Kaneko
  • Shoji Tsuji
  • Masafumi Hasui
  • Seiji Kanda
  • Toshimasa Nishiyama
Original Article


The pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear. To study the role of nitric oxide (NO) in INS, we measured intracellular NO produced by T- and B-cells using a novel fluorescent indicator. Twelve children with INS (mean age 7.3 years; group A-1: in relapse, group A-2: in remission) were enrolled in the study together with 16 children with other renal diseases (9.5 years; group B) and 42 healthy control children (7.7 years; group C). The amount of NO produced by CD3+ cells (T-cells) and CD19+ cells (B-cells) and of plasma NOx was measured by flow cytometry and colorimetry, respectively. The average amount of NO produced by CD3+ and CD19+ cells in group A-1 subjects was significantly higher than that produced by these cells in group A-2 and B patients and the healthy controls (group C), respectively (P < 0.01), and it decreased after the patients achieved remission (P < 0.01). Plasma NOx levels in group A-1 patients was also highest among the different groups (P < 0.01). There were no significant differences in intracellular NO and plasma NOx among group A-2, B, and C subjects (P > 0.05). A significant correlation between plasma NOx and urinary protein excretion was found only in group A patients and not in group B patients. We conclude that an aberrant immune system may exist not only in T-cells but also in B-cells, and NO may play some role in INS.


B-cell CD3+ CD19+ Idiopathic nephrotic syndrome Nitric oxide T-cell 


  1. 1.
    Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 7:556–560CrossRefGoogle Scholar
  2. 2.
    Araya CE, Wasserfall CH, Brusko TM, Mu W, Segal MS, Johnson RJ, Garin EH (2006) A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 21:603–610PubMedCrossRefGoogle Scholar
  3. 3.
    Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–2752PubMedCrossRefGoogle Scholar
  4. 4.
    Dötsch J, Müller-Wiefel DE, Kemper MJ (2008) Rituximab: is replacement of cyclophosphamide and calcineurin inhibitors in steroid-dependent nephrotic syndrome possible. Pediatr Nephrol 23:3–7PubMedCrossRefGoogle Scholar
  5. 5.
    Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F (2008) Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol 23:1269–1279PubMedCrossRefGoogle Scholar
  6. 6.
    Kemper MJ, Meyer-Jark T, Lilova M, Müller-Wiefel DE (2003) Combined T- and B-cell activation in childhood steroid-sensitive nephrotic syndrome. Clin Nephrol 60:242–247PubMedGoogle Scholar
  7. 7.
    Lapillonne H, Leclerc A, Ulinski T, Balu L, Garnier A, Dereuddre-Bosquet N, Watier H, Schlageter MH, Deschênes G (2008) Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome. Pediatr Nephrol 23:1251–1256PubMedCrossRefGoogle Scholar
  8. 8.
    Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood. Lancet 23:629–639CrossRefGoogle Scholar
  9. 9.
    Maruyama K, Tomizawa S, Shimabukuro N, Fukuda T, Johshita T, Kuroume T (1989) Effect of supernatants derived from T lymphocyte culture in minimal change nephrotic syndrome on rat kidney capillaries. Nephron 51:73–76PubMedCrossRefGoogle Scholar
  10. 10.
    Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M (1991) A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 40:453–460PubMedCrossRefGoogle Scholar
  11. 11.
    Kemper MJ, Wolf G, Müller-Wiefel DE (2001) Transmission of glomerular permeability factor from a mother to her child. N Engl J Med 344:386–387PubMedCrossRefGoogle Scholar
  12. 12.
    Balat A, Cekmen M, Yürekli M, Gülcan H, Kutlu O, Türköz Y, Yologlu S (2000) Adrenomedullin and nitrite levels in children with minimal change nephrotic syndrome. Pediatr Nephrol 15:70–73PubMedCrossRefGoogle Scholar
  13. 13.
    Kawashima H, Kashiwagi Y, Watanabe C, Sato S, Nishimata S, Takekuma K, Hoshika A, Watanabe Y (2007) NOx (nitrite/nitrate) in patients with pediatric nephrotic syndrome. Pediatr Nephrol 22:840–843PubMedCrossRefGoogle Scholar
  14. 14.
    Trachtman H, Gauthier B, Frank R, Futterweit S, Goldstein A, Tomczak J (1996) Increased urinary nitrite excretion in children with minimal change nephrotic syndrome. J Pediatr 128:173–176PubMedCrossRefGoogle Scholar
  15. 15.
    Trachtman H (2004) Nitric oxide and glomerulonephritis. Semin Nephrol 24:324–332PubMedCrossRefGoogle Scholar
  16. 16.
    Bachmann S, Mundel P (1994) Nitric oxide in the kidney: synthesis, localization, and function. Am J Kidney Dis 24:112–129PubMedGoogle Scholar
  17. 17.
    Kojima H, Nakatsubo N, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, Hirata Y, Nagano T (1998) Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins. Anal Chem 70:2446–2453PubMedCrossRefGoogle Scholar
  18. 18.
    Kojima H, Urano Y, Kikuchi K, Higuchi T, Hirata Y, Nagano T (1999) Fluorescent indicators for imaging nitric oxide production. Angew Chem Int Ed Engl 38:3209–3212PubMedCrossRefGoogle Scholar
  19. 19.
    Itoh Y, Ma FH, Hoshi H, Oka M, Noda K, Ukai Y, Kojima H, Nagano T, Toda N (2000) Determination and bioimaging method for nitric oxide in biological specimens by diaminofluorescein fluorometry. Anal Biochem 287:203–209PubMedCrossRefGoogle Scholar
  20. 20.
    Tsuji S, Taniuchi S, Hasui M, Yamamoto A, Kobayashi Y (2002) Increased nitric oxide production by neutrophils from patients with chronic granulomatous disease on trimethoprim-sulfamethoxazole. Nitric Oxide 7:283–288PubMedCrossRefGoogle Scholar
  21. 21.
    Someya T, Kaneko K, Yamada T, Yamashiro Y (2005) Effect of a novel free radical scavenger, edaravone, on puromycin aminonucleoside induced nephrosis in rats. Pediatr Nephrol 20:1430–1434PubMedCrossRefGoogle Scholar
  22. 22.
    Sellier-Leclerc AL, Duval A, Riveron S, Macher MA, Deschenes G, Loirat C, Verpont MC, Peuchmaur M, Ronco P, Monteiro RC, Haddad E (2007) A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol 18:2732–2739PubMedCrossRefGoogle Scholar
  23. 23.
    Csont T, Bereczki E, Bencsik P, Fodor G, Görbe A, Zvara A, Csonka C, Puskás LG, Sántha M, Ferdinandy P (2007) Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice. Cardiovasc Res 76:100–109PubMedCrossRefGoogle Scholar
  24. 24.
    Ni Z, Vaziri ND (2003) Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. Biochim Biophys Acta 1638:129–137PubMedGoogle Scholar

Copyright information

© IPNA 2009

Authors and Affiliations

  • Anna Iharada
    • 1
  • Kazunari Kaneko
    • 1
  • Shoji Tsuji
    • 1
  • Masafumi Hasui
    • 1
  • Seiji Kanda
    • 2
  • Toshimasa Nishiyama
    • 2
  1. 1.Department of PediatricsKansai Medical UniversityHirakata-shi, OsakaJapan
  2. 2.Public HealthKansai Medical UniversityOsakaJapan

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