Advertisement

Pediatric Nephrology

, Volume 21, Issue 8, pp 1082–1092 | Cite as

Compensatory renal growth protects mice against Shiga toxin 2-induced toxicity

  • Gabriela Verónica CameranoEmail author
  • Oscar David Bustuoabad
  • Roberto Pablo Meiss
  • Sonia Alejandra Gómez
  • Gabriela Cristina Fernández
  • Martín Amadeo Isturiz
  • Marina Sandra Palermo
  • Graciela Isabel Dran
Original Article

Abstract

Uninephrectomy (Unx) is followed by the compensatory renal growth (CRG) of the remaining kidney. Previous evidence has shown that during CRG, renal tissue is resistant to a variety of pathologies. We tested the hypothesis that the functional changes that take place during CRG could attenuate Shiga toxin (Stx) toxicity in a mouse model of Stx2-induced hemolytic uremic syndrome (HUS). The participation of nitric oxide (NO) was analyzed. After CRG induction with Unx, mice were exposed to a lethal dose of Stx2, and the degree of renal damage and mortality was measured. Stx2 effects on the growth, renal blood flow (RBF) and NO synthase (NOS) intrarenal expression in the remaining kidney were then studied. The induction of CRG strongly prevented Stx2-mediated mortality and renal damage. Administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) during CRG partially impaired the protection. Both Stx2 and L-NAME interfered with the hypertrophic and hyperplastic responses to Unx, as well as with the increase in RBF. In intact mice, Stx2 decreased renal perfusion, inhibited endothelial NOS basal expression and enhanced inducible NOS expression; all of these effects were attenuated by prior Unx. It is concluded that during CRG mice are highly protected against Stx2 toxicity and lethality. The protective capacity of CRG could be related to the enhancement of renal perfusion and preservation of eNOS renal expression, counterbalancing two major pathogenic mechanisms of Stx2.

Keywords

Uninephrectomy Compensatory renal growth Shiga toxin Hemolytic uremic syndrome 

Notes

Acknowledgements

We thank Dr. Carlos Amorena, University of San Martin Bs. As., for his critical review of the manuscript, and Vet. Hector Costa for excellent technical assistance. This work was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación “Alberto J. Roemmers” and Agencia Nacional de Promoción Científica y Tecnológica, Argentina.

References

  1. 1.
    Fine L (1986) The biology of renal hypertrophy. Kidney Int 29:619–634PubMedCrossRefGoogle Scholar
  2. 2.
    Wolf G, Neilson EG (1991) Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia. Kidney Int 39:401–420PubMedCrossRefGoogle Scholar
  3. 3.
    Johnson H, Vera Roman JM (1966) Compensatory renal enlargement. Am J Pathol 49:1–13PubMedGoogle Scholar
  4. 4.
    Lopez-Novoa JM, Ramos B, Martín-Oar JE, Hernando L (1982) Functional compensatory changes after unilateral nephrectomy in rats. General and intrarenal hemodynamic alterations. Renal Physiol 5:76–84PubMedGoogle Scholar
  5. 5.
    Ring K, Benson M, Bandyk M, Sawczuk I (1992) Detection of cellular proliferation during compensatory renal growth using flow cytometry. Nephron 61:200–203PubMedGoogle Scholar
  6. 6.
    Ramos B, López-Novoa JM, Hernando L (1982) Role of hemodynamic alterations in the partial protection afforded by uninephrectomy against glycerol-induced acute renal failure in rats. Nephron 30:68–72PubMedCrossRefGoogle Scholar
  7. 7.
    Fried TA, Hishida A, Barnes JL, Stein JH (1984) Ischemic acute renal failure in the rat: Protective effect of uninephrectomy. Am J Physiol 247:568–574Google Scholar
  8. 8.
    Nakajima T, Miyaji T, Kato A, Ikegaya N, Yamamoto T, Hishida A (1996) Uninephrectomy reduces apoptotic cell death and enhances renal tubular regeneration in ischemic ARF in rats. Am J Physiol 271:846–853Google Scholar
  9. 9.
    Kato A, Hishida A, Nakajima T (1995) Role of thromboxane A2 and prostacyclin in uninephrectomy-induced attenuation of ischemic renal injury. Kidney Int 48:1577–1583Google Scholar
  10. 10.
    Kato A, Hishida A, Tanaka I, Komatsu K (1997) Uninephrectomy prevents the ischemia induced increase in renin activity. Nephron 75:72–76PubMedGoogle Scholar
  11. 11.
    Kato A, Hishida A (2001) Amelioration of post-ischaemic renal injury by contralateral uninephrectomy: a role of endothelin-1. Nephrol Dial Transplant 16:1570–1576PubMedCrossRefGoogle Scholar
  12. 12.
    Ray PE, Liu XH (2001) Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome. Pediatr Nephrol 16:823–839PubMedCrossRefGoogle Scholar
  13. 13.
    Obrig TG (1997) Shiga toxin mode of action in E. coli O157:H7 disease. Front Biosci 2:635–642Google Scholar
  14. 14.
    Karmali MA (2004) Infection by Shiga toxin-producing Escherichia coli: an overview. Mol Biotechnol 26:117–122PubMedCrossRefGoogle Scholar
  15. 15.
    Cotran RS, Kumar V, Collins T (1999) Robbin’s pathologic basis of disease. WB Saunders, Philadelphia, PA, pp 969Google Scholar
  16. 16.
    Fernandez GC, Te Loo MW, van der Velden TJ, van der Heuvel LP, Palermo MS, Monnens LL (2003) Decrease in thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome. Pediatr Nephrol 18:1066–1068PubMedCrossRefGoogle Scholar
  17. 17.
    Te Loo M, Bosma N, Van Hinsbergh V, Span P, De Waal R, Clarijs R, Sweep C, Monnens L, van der Heuvel L (2004) Elevated levels of vascular endothelial growth factor in serum of patients with D-HUS. Pediatr Nephrol 19:754–760CrossRefGoogle Scholar
  18. 18.
    Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  19. 19.
    Morris SM, Billiar TR (1994) New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266:829–839Google Scholar
  20. 20.
    Noris M, Ruggenenti P, Todeschini M, Figliuzzi M, Macconi D, Zoja C, Paris S, Gaspari F, Remuzzi G (1996) Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury. Am J Kidney Dis 27:790–796PubMedCrossRefGoogle Scholar
  21. 21.
    Dran G, Fernández GC, Rubel CJ, Bermejo E, Gomez S, Isturiz MA, Palermo M (2002) Participation of L-arginine-nitric oxide pathway in the pathogenesis of hemolytic uremic syndrome in a murine model. Kidney Int 62:1338–1348PubMedCrossRefGoogle Scholar
  22. 22.
    Valdivielso JM, Perez-Barriocanal F, García-Estan J, López-Novoa JM (1999) Role of nitric oxide in the early renal hemodynamic response after unilateral nephrectomy. Am J Physiol 276:1718–1723Google Scholar
  23. 23.
    Sigmon DH, Gonzalez-Feldman E, Cavasin MA, Potter DL, Beierwaltes WH (2004) Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy. J Am Soc Nephrol 15:1413–1420PubMedCrossRefGoogle Scholar
  24. 24.
    Tolins JP, Palmer RM, Moncada S, Raij L (1990) Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 258:655–662Google Scholar
  25. 25.
    Raij L, Baylis C (1995) Glomerular actions of nitric oxide. Kidney Int 48:20–32PubMedCrossRefGoogle Scholar
  26. 26.
    Perico N, Remuzzi G (2002) Nitric oxide and renal perfusion in humans. J Hypertens 20:391–393PubMedCrossRefGoogle Scholar
  27. 27.
    Jansen A, Cook T, Michael T, Largen P, Riveros MV, Moncada S, Cattell V (1994) Induction of nitric oxide synthase in rat immune complex glomerulonephritis. Kidney Int 45:1215–1219PubMedCrossRefGoogle Scholar
  28. 28.
    Furusu A, Miyasaki M, Abe K, Tsukasaki S, Shioshita K, Sasaki O, Miyasaki K, Ozono Y, Koji T, Harada T, Sakai H, Kohno S (1998) Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int 53:1760–1768PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou XI, Laszik Z, Ni Z, Wang XQ, Brackett DJ, Lerner MR, Silva FG, Vaziri ND (2000) Down regulation of renal endothelial nitric oxide synthase expression in experimental glomerular thrombotic microangiopathy. Lab Invest 80:1079–1087PubMedGoogle Scholar
  30. 30.
    Palermo MS, Alves Rosa MF, Rubel C, Fernández GC, Fernández Alonso G, Alberto F, Rivas M, Isturiz MA (2000) Pretreatment of mice with lipopolysaccharide (LPS) or IL1β exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol 119:77–83Google Scholar
  31. 31.
    National Institutes of Health (NIH) (1985) Guide for the care and use of laboratory animals. Government Printing Office, Washington, DCGoogle Scholar
  32. 32.
    Orucevic A, Lala PK (1996) N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumor growth in adenocarcinoma-bearing mice. Br J Cancer 73:189–196PubMedGoogle Scholar
  33. 33.
    Bradford MM (1976) A rapid and sensitive method for the quantification of microgram of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  34. 34.
    Kasina S, Fritzberg AR, Johnson DL, Eshima D (1986) Tissue distribution properties of technetium-99m-diamide-dimercaptide complexes and potential use as a renal radiopharmaceutical. J Med Chem 29:1933–1940PubMedCrossRefGoogle Scholar
  35. 35.
    Ercan MT, Gulaldi NC, Unsal IS, Aydin M, Peksoy I, Hascelik Z (1996) Evaluation of Tc-99m (V) DMSA for imaging inflammatory lesions: an experimental study. Ann Nucl Med 10:419–423PubMedCrossRefGoogle Scholar
  36. 36.
    Rosignoli F, Goren N, Perez Leirós C (1986) Alterations in nitric oxide synthase activity and expression in submandibular glands of NOD mice. Clin Immunol 101:86–93CrossRefGoogle Scholar
  37. 37.
    Ikeda M, Ito S, Honda M (2004) Hemolytic uremic syndrome induced by lipopolysaccharide and Shiga-like toxin. Pediatr Nephrol 19:485–489PubMedCrossRefGoogle Scholar
  38. 38.
    Obrig TG, Del Vecchio PJ, Brown JE, Moran TP, Rowland BM, Judge TK, Rothman SW (1988) Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. Infect Immun 56:2373–2378PubMedGoogle Scholar
  39. 39.
    Majoul I, Schmidt T, Pomasanova M, Boutkevich E, Kozlov Y, Soling HD (2002) Differential expression of receptors for Shiga and Cholera toxins is regulated by the cell cycle. J Cell Sci 115:817–826PubMedGoogle Scholar
  40. 40.
    Scholbach TM (1986) Changes of renal flow volume in the hemolytic uremic syndrome—Color Doppler sonographic investigations. Pedriatr Nephrol 16:644–647Google Scholar
  41. 41.
    West JB (1991) Physiological basis of medical practice, 12th edn. Waverly, Baltimore, MD, pp 530Google Scholar
  42. 42.
    Barger AC, Herd JA (1971) The renal circulation. N Engl J Med 284:482–490PubMedCrossRefGoogle Scholar
  43. 43.
    Karlberg L, Norlen BJ, Ojteg G, Wolgast M (1983) Impaired medullary circulation in postischemic acute renal failure. Acta Physiol Scand 118:11–17PubMedCrossRefGoogle Scholar
  44. 44.
    Brezis MS, Rosen S, Silva RP, Epstein FH (1984) Renal ischemia. A new perspective. Kidney Int 26:375–383PubMedCrossRefGoogle Scholar
  45. 45.
    Schwartz D, Mendonca M, Schwartz I, Xia Y, Satriano J, Wilson CB, Blantz RC (1997) Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest 100:439–448PubMedCrossRefGoogle Scholar
  46. 46.
    Williams JM, Lote CJ, Thewels A, Wood JA, Howie AJ, Williams DA, Taylor M (2000) Role of nitric oxide in a toxin-induced model of haemolytic uremic syndrome. Pediatr Nephrol 14:1066–1070PubMedCrossRefGoogle Scholar
  47. 47.
    Aka JA, Jelacic S, Ciol MA, Watkins SL, Murray KF, Christie DL, Klein EJ, Tarr PI (2005) Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion. Pediatrics 115:e673–e680CrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Gabriela Verónica Camerano
    • 1
    • 4
    Email author
  • Oscar David Bustuoabad
    • 1
  • Roberto Pablo Meiss
    • 2
  • Sonia Alejandra Gómez
    • 3
  • Gabriela Cristina Fernández
    • 3
  • Martín Amadeo Isturiz
    • 3
  • Marina Sandra Palermo
    • 3
  • Graciela Isabel Dran
    • 1
  1. 1.Sección Medicina ExperimentalAcademia Nacional de MedicinaBuenos AiresArgentina
  2. 2.Departamento de Patología, Centro de Estudios OncológicosAcademia Nacional de MedicinaBuenos AiresArgentina
  3. 3.Sección InmunologíaAcademia Nacional de MedicinaBuenos AiresArgentina
  4. 4.División Medicina Experimental, ILEX,Academia Nacional de MedicinaBuenos AiresArgentina

Personalised recommendations