ROLE OF NITRIC-OXIDE IN RAT NEPHROTOXIC NEPHRITIS - COMPARISON BETWEEN INDUCIBLE AND CONSTITUTIVE NITRIC-OXIDE SYNTHASE

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrat ing macrophages, is increased in glomerulonephritis. This study invest igates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was ind uced in Sprague Dawley rats by an injection of an anti-glomerular base ment membrane (GEM) antibody. Urinary nitrite excretion and nitrite re lease from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg p rotein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increas ed in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS ) expression evaluated by counting immunogold particles along GEM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/mu m GEM, P < 0.00 01). Glomerular damage developed progressively. N-G-nitro-L-arginine m ethyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguan idine (AG), a relatively selective inhibitor for iNOS, equally suppres sed nitrite in urine and renal tissue. Glomerular ICAM-1 expression an d macrophage infiltration were reduced by L-NAME, but not by AG, Expre ssion of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04), AG signific antly and L-NAME slightly attenuated the glomerular damage at day 4. I n conclusion, suppression of iNOS prevents glomerular damage in the ea rly stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an incr ease in ecNOS expression.