Induced nitric oxide (NO) synthesis in heterologous nephrotoxic nephritis; effects of selective inhibition in neutrophil-dependent glomerulonephritis.
Increased NO synthesis, due to inducible NO synthase (iNOS) activity, is found in macrophage-associated glomerulonephritis. Little is known about NO in neutrophil-dependent immune complex inflammation, and its role remains controversial. We therefore studied early phase heterologous nephrotoxic nephritis (HNTN) induced in rats by nephrotoxic globulin and the effects of selective iNOS inhibition of this model. At 2 h of the model iNOS mRNA was induced and nitrite (NO-2) was generated in glomeruli incubated ex vivo (5.2 +/- 1.0 nmol/2000 glomeruli per 24 h). There were 14.7 +/- 2.2 polymorphonuclear neutrophils (PMN)/glomerulus (normal controls 0.1 +/- 0.1). At 8 h urinary protein was 69 +/- 15.3 (normal controls 0. 6 +/- 0.2 mg/24 h). Peritoneal PMN expressed iNOS and produced significant NO-2 (basal 11.2 +/- 0.3 nmol/106 cells per 24 h). Selective iNOS inhibition with L-N6-(1-iminoethyl)-lysine (L-NIL) in vitro inhibited nephritic glomerular and PMN NO-2 synthesis. In HNTN L-NIL in vivo significantly suppressed elevated plasma NO-2/NO-3 levels (representative experiment: 17 +/- 2 microM, untreated 40 +/- 4 microM, P = < 0.01, normal control 18 +/- 2 microM). This inhibition did not affect leucocyte infiltration into glomeruli or induce thrombosis. There was no consistent effect on proteinuria. This is the first demonstration of glomerular iNOS induction and high output NO production in the acute phase of PMN-dependent acute immune complex glomerulonephritis. Selective iNOS inhibition does not affect the primary mechanism of injury (leucocyte infiltration) in this model.
Waddington
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SN
Department of Histopathology, Imperial College School of Medicine at St Mary's, London, UK.
Mosley
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K
Cattell
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D000818:Animals; D004790:Enzyme Induction / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005921:Glomerulonephritis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology*; D026541:Heymann Nephritis Antigenic Complex; D007678:Kidney Glomerulus / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew
D004791:Enzyme Inhibitors; D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; C090663:N(6)-(1-iminoethyl)lysine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine