Nitric oxide synthase expression in AT2 receptor–deficient mice after DOCA-salt

Nitric oxide synthase expression in AT 2 receptor–deficient mice after DOCA-salt. Background Angiotensin II type 2 receptor–deficient mice (AT 2 -/y) provide an opportunity to study the relationship between the angiotensin II type 1 receptor (AT 1 ) and nitric oxide synthase (NOS) isoforms without concomitant AT 2 receptor–related effects. To test this relationship, the expression of renal NOS isoforms (neural, inducible, and endothelial) in AT 2 -/y and AT 2 +/y mice was examined. The mice were challenged with deoxycorticosterone acetate (DOCA)-salt to stimulate NO generation. Methods Gene expression analyses by real-time polymerase chain reaction (PCR) (TaqMan) were performed in kidneys to characterize neuronal nitric oxide synthase (nNOS), epithelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and the AT 1 receptor. Pressure-natriuresis experiments were done to determine the physiologic background. Results AT 2 -/y mice showed nNOS and iNOS up-regulation. DOCA-salt increased iNOS expression more in AT 2 -/y mice than in AT 2 +/y mice. Immunohistochemistry localized the iNOS expression with DOCA-salt mainly in the glomeruli. eNOS was not different between the groups, and was not affected by DOCA-salt. DOCA-salt increased mean arterial pressure more in AT 2 -/y mice than in AT 2 +/y mice. Concomitantly, the pressure-natriuresis relationship was shifted to the right in AT 2 -/y and AT 2 +/y mice after DOCA-salt. DOCA-salt decreased renal blood flow (RBF) and glomerular filtration rate (GFR) in both groups. iNOS blockade did not lower blood pressure. Conclusion We conclude that AT 2 receptor deletion and concomitant up-regulation of the AT 1 receptor is associated with up-regulation of nNOS and iNOS. Under DOCA-salt, renal iNOS expression was further increased. Because iNOS inhibition did not change blood pressure, iNOS may not be involved in the hemodynamics, but may contribute to organ damage.