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Publication Detail
L-Arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    JOUR
  • Authors:
    Waddington S, Cook HT, Reaveley D, Jansen A, Cattell V
  • Publication date:
    1996
  • Pagination:
    1090, 1096
  • Volume:
    49
  • Notes:
    Arginase NO synthesis is induced in glomeruli in gn; its role in the pathogenesis of glomerular injury is unknown. Interpretation of its role using the currently available analogues of L-arginine as in vivo inhibitors of NO is complicated by their lack of specificity for iNOS. As NO synthesis by iNOS depends on extracellular arginine, we have here examined effects of L-arginine depletion on glomerular NO synthesis and the course of ANTN. Arginase, which converts arginine to urea and ornithine, was used to achieve arginine depletion. A single dose of i.v. arginase produced complete depletion of plasma arginine for four hours. Two forms of NTN were induced in preimmunised rats by NTG: 1) the systemic form of the model by i.v. NTG; or 2) the unilateral form of model by left kidney perfusion with NTG, which avoids the complications of systemic administration of NTG. Arginase reduced plasma arginine levels and the synthesis of nitrite (the stable end-product of NO) by NTN glomeruli (95% inhibition). Proteinuria was exacerbated. There was no effect on early (24h) leukocyte infiltration. In the systemic form of the model arginine depletion by i.v. arginase increased glomerular thrombosis at 24 hours, and the severity of histological changes at four days, accompanied by systemic hypertension. In the unilateral form of the model, where i.v. arginase did not induce hypertension, there was no increase in thrombosis or histological severity of nephritis. These results show that arginine depletion, which inhibits glomerular NO synthesis in NTN, leads to increased proteinuria. Where injury is severe, or accompanied by systemic hypertension, the disease is further exacerbated by glomeular thrombosis. These results suggest that NO has an important role in limiting acute glomerular injury.
Abstract
NO synthesis is induced in glomeruli in gn; its role in the pathogenesis of glomerular injury is unknown. Interpretation of its role using the currently available analogues of L-arginine as in vivo inhibitors of NO is complicated by their lack of specificity for iNOS. As NO synthesis by iNOS depends on extracellular arginine, we have here examined effects of L-arginine depletion on glomerular NO synthesis and the course of ANTN. Arginase, which converts arginine to urea and ornithine, was used to achieve arginine depletion. A single dose of i.v. arginase produced complete depletion of plasma arginine for four hours. Two forms of NTN were induced in preimmunised rats by NTG: 1) the systemic form of the model by i.v. NTG; or 2) the unilateral form of model by left kidney perfusion with NTG, which avoids the complications of systemic administration of NTG. Arginase reduced plasma arginine levels and the synthesis of nitrite (the stable end-product of NO) by NTN glomeruli (95% inhibition). Proteinuria was exacerbated. There was no effect on early (24h) leukocyte infiltration. In the systemic form of the model arginine depletion by i.v. arginase increased glomerular thrombosis at 24 hours, and the severity of histological changes at four days, accompanied by systemic hypertension. In the unilateral form of the model, where i.v. arginase did not induce hypertension, there was no increase in thrombosis or histological severity of nephritis. These results show that arginine depletion, which inhibits glomerular NO synthesis in NTN, leads to increased proteinuria. Where injury is severe, or accompanied by systemic hypertension, the disease is further exacerbated by glomeular thrombosis. These results suggest that NO has an important role in limiting acute glomerular injury.
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