INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE INTENSIFIES INJURY AND FUNCTIONAL DETERIORATION IN AUTOIMMUNE INTERSTITIAL NEPHRITIS

T lymphocytes are exquisitely sensitive to the antiproliferative effec ts of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, N-w-nitro-L-arginine methyl este r (L-NAME) and L-N-6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expr essed in cortical tubular epithelial cells. Treatment with either inhi bitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L -NlL, a highly selective inhibitor of iNOS, were not. Evaluation of th e expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quant itative reverse transcriptase-PCR demonstrated that L-NAME-treated ani mals displayed significantly augmented levels of lFN-gamma and IL-2 wi th preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treat ed animals had augmented levels of IL-2 and IFN-gamma with augmented I FN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-N IL both had augmented Ag-specific Ige responses. The L-NAME group demo nstrated increases in both the IgG2a and IgG1 subtypes, with a constan t IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data sugge st that the L-NIL-treated animals had a skewing of their immune respon se toward a Th1-like response. We conclude that in autoimmune intersti tial nephritis, generation of nitric oxide through the iNOS pathway ha s host-protective effects, and suggest that this may be broadly applic able to T cell-mediated pathologies.