L-ARGININE DEPLETION INHIBITS GLOMERULAR NITRIC-OXIDE SYNTHESIS AND EXACERBATES RAT NEPHROTOXIC NEPHRITIS

Nitric oxide (NO) synthesis is induced in glomeruli in glomerulonephri tis; its role in the pathogenesis of glomerular injury is unknown. Int erpretation of its role using the currently available analogues of L-a rginine as in vivo inhibitors of NO is complicated by their lack of sp ecificity for inducible NO synthase (iNOS). As NO synthesis by iNOS de pends on extracellular L-arginine, we have here examined effects of L- arginine depletion on glomerular NO synthesis and the course of accele rated nephrotoxic nephritis (NTN). Arginase, which converts L-arginine to urea and L-ornithine, was used to achieve L-arginine depletion. A single dose of i.v. arginase produced complete depletion of plasma arg inine for four hours. Two forms of NTN were induced in preimmunised ra ts by nephrotoxic globulin: (1) the systemic form of the model by intr avenous nephrotoxic globulin; or (2) the unilateral form of model by l eft kidney perfusion with nephrotoxic globulin, which avoids the compl ications of systemic administration of nephrotoxic globulin. Arginase reduced plasma arginine levels and the synthesis of nitrite (the stabl e end-product of NO) by NTN glomeruli (95% inhibition). Proteinuria wa s exacerbated. There was no effect on early (24 hr) leukocyte infiltra tion. In the systemic form of the model arginine depletion by i.v. arg inase increased glomerular thrombosis at 24 hours, and the severity of histological changes at four days, accompanied by systemic hypertensi on. In the unilateral form of the model, where i.v. arginase did not i nduce hypertension, there was no increase in thrombosis or histologica l severity of nephritis. These results show that arginine depletion, w hich inhibits glomerular NO synthesis in NTN, leads to increased prote inuria. Where injury is severe, or accompanied by systemic hypertensio n, the disease is further exacerbated by glomerular thrombosis. These results suggest that NO has an important role in limiting acute glomer ular injury.