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-orni thine. Inflammatory responses may involve a balance between the pathwa ys, as NO is cytotoxic and vasodilatory and L-ornithine is a promoter of cell proliferation and matrix synthesis. In experimental glomerulon ephritis we have previously shown that NOS is activated in nephritic g lomeruli. We have now examined both pathways of L-arginine metabolism to study competition for L-arginine, temporal variation, and the sourc es of NOS and arginase. Acute in situ glomerulonephritis was induced i n rats, and glomeruli were studied at 1, 4, and 7 days. Both NOS and a rginase activities were present. There was temporal variation: NOS act ivity was highest on day 2 and arginase activity on day 4; both declin ed by day 7. Competition between the pathways was demonstrated by incr eased urea synthesis in the presence of N-G-monomethyl-L-arginine, an inhibitor of NOS. Measurement of NOS and arginase activities in macrop hages 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 cultu red rat glomerular mesangial cells. These studies show differential te mporal variation in expression of NOS and arginase pathways of arginin e metabolism in experimental glomerulonephritis. We have found two fac tors that may contribute to this: 1) competition for substrate L-argin ine between the two pathways and 2) different cellular sources. We hyp othesize that the balance between these pathways is a mechanism regula ting injury, hemodynamics, and mesangial cell proliferation.