35 OXIDATIVE STRESS-INDUCED GLOMERULAR MINERALOCORTICOID RECEPTOR ACTIVATION LIMITS THE BENEFIT OF SALT REDUCTION IN DAHL SALT-SENSITIVE HYPERTENSIVE RATS

Abstract

Background: Mineralocorticoid receptor antagonists attenuate renal injury in salt-sensitive hypertensive rats, which have low plasma aldosterone levels. We hypothesized that oxidative stress causes mineralocorticoid receptor activation in the kidney regardless of plasma aldosterone level, and that activated mineralocorticoid receptor could affect renal function in Dahl salt-sensitive rats, even after switching from a high- to a normal-salt diet. Methods and Results: High-salt feeding for 4 weeks increased the dihydroethidium fluorescence (DHE, an oxidant production marker), p22phox (an NADPH oxidase subunit) and serum and glucocorticoid-regulated kinase-1 (an MR transcript) in glomeruli compared with normal-salt feeding, and these changes persisted at 4 weeks after salt withdrawal. Tempol treatment (0.5 mmol/L) during high-salt feeding abolished the changes in DHE and p22phox and serum and glucocorticoid-regulated kinase-1, but did not affect high-salt-feeding-induced increases in blood pressure and proteinuria during that period. Dietary salt reduction after a 4-week high-salt diet decreased both blood pressure and proteinuria, but was associated with significantly higher proteinuria than in normal control rats at 4 weeks after salt reduction. Tempol during high-salt feeding, or eplerenone, a mineralocorticoid receptor antagonist (100 mg/kg/day), started after salt reduction, recovered proteinuria to normal levels by 4 weeks after salt reduction. Paraquat, a reactive oxygen species generator, enhanced mineralocorticoid receptor transcriptional activity in cultured rat mesangial cells and mouse podocytes. Conclusions: These results suggest that oxidative stress in the kidney plays an important role in glomerular mineralocorticoid receptor activation in Dahl salt-sensitive rats. Persistent mineralocorticoid receptor activation even after reducing salt intake could limit the beneficial effects of salt restriction.