Arginine metabolism in experimental glomerulonephritis: interaction between nitric oxide synthase and arginase.
L-Arginine is metabolized by two pathways: 1) by nitric oxide synthase (NOS) to nitric oxide (NO) and 2) by arginase forming urea and L-ornithine. Inflammatory responses may involve a balance between the pathways, as NO is cytotoxic and vasodilatory and L-ornithine is a promoter of cell proliferation and matrix synthesis. In experimental glomerulonephritis we have previously shown that NOS is activated in nephritic glomeruli. We have now examined both pathways of L-arginine metabolism to study competition for L-arginine, temporal variation, and the sources of NOS and arginase. Acute in situ glomerulonephritis was induced in rats, and glomeruli were studied at 1, 4, and 7 days. Both NOS and arginase activities were present. There was temporal variation: NOS activity was highest on day 1 and arginase activity on day 4; both declined by day 7. Competition between the pathways was demonstrated by increased urea synthesis in the presence of NG-monomethyl-L-arginine, an inhibitor of NOS. Measurement of NOS and arginase activities in macrophages isolated from nephritic glomeruli showed that these cells were a major source of glomerular NOS but not arginase activity. In contrast, high arginase activity but low NO production was identified in cultured rat glomerular mesangial cells. These studies show differential temporal variation in expression of NOS and arginase pathways of arginine metabolism in experimental glomerulonephritis. We have found two factors that may contribute to this: 1) competition for substrate L-arginine between the two pathways and 2) different cellular sources. We hypothesize that the balance between these pathways is a mechanism regulating injury, hemodynamics, and mesangial cell proliferation.
Cook
H T
HT
Department of Histopathology, St. Mary's Hospital Medical School, London, United Kingdom.
Jansen
A
A
Lewis
S
S
Largen
P
P
O'Donnell
M
M
Reaveley
D
D
Cattell
V
V
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology; D005921:Glomerulonephritis / Q000201:enzymology*; D006801:Humans; D007074:Immunoglobulin G; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D014508:Urea / Q000378:metabolism; D019323:omega-N-Methylarginine
D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009573:Nitrites; D019323:omega-N-Methylarginine; D014508:Urea; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D001119:Arginase