PPAR agonists were shown to inhibit atherosclerosis through augmentation of endothelial NOS activity. In addition, rosiglitazone exerts a beneficial effect in CRF. Since L-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings were studied in: Control animals; rats, six weeks following 5/6 nephrectomy (CRF); and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF, but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKC and phosphorylated CAT-1 increased significantly in CRF, effects which were prevented by rosiglitazone. PKC phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of Phorbol-12-myristate-13-acetate to rosiglitazone treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to Carbamyl-Choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats, and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKC. Theses findings are associated with restoration of endothelial NO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia.