AUTOCRINE INHIBITION OF NA+/K+-ATPASE BY NITRIC-OXIDE IN MOUSE PROXIMAL TUBULE EPITHELIAL-CELLS

An inducible nitric oxide synthase has recently been described in proximal tubule epithelium To investigate the effects of proximal tubule NO on Na+/K+-ATPase, we induced NO production in mouse proximal tubule epithelial cells by treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN gamma) followed by determinations of ouabain-sensitive ATPase activity, Na+/K+-ATPase activity decreased after 4 h of IPS/IFN gamma treatment, reaching maximal inhibition after 24 h (34% reduction in activity), The inhibition of Na+/K+-ATPase activity by LPS/IFN gamma was prevented by simultaneous incubation with N-omega-nitro L-arginine and markedly blunted by removal of L-arginine from the medium, The NO donors sodium nitroprusside and SIN-1 also inhibited Na+/K+-ATPase activity to a similar extent than LPS/IFN gamma. However, treatment with 8-pCPT-cGMP only modestly reduced Na+/K+-ATPase activity. Interestingly, superoxide dismutase prevented the inhibitory effects of NO on Na+/K+-ATPase activity, suggesting a role for peroxynitrite in this inhibition, We conclude that NO generated by mouse proximal tubule epithelial cell iNOS inhibits Na/K ATPase activity in an autocrine fashion and that this inhibition is accompanied by a reduction in Na-dependent solute transport.