Abstract
BackgroundMineralocorticoid receptor (MR) antagonists attenuate renal injury in salt-sensitive hypertensive rats with low plasma aldosterone levels. We hypothesized that oxidative stress causes MR activation in high-salt-fed Dahl salt-sensitive rats. Furthermore, we determined if MR activation persisted and induced renal injury, even after switching from a high- to a normal-salt diet.Methods and FindingsHigh-salt feeding for 4 weeks increased dihydroethidium fluorescence (DHE, an oxidant production marker), p22phox (a NADPH oxidase subunit) and serum and glucocorticoid-regulated kinase-1 (SGK1, an MR transcript) in glomeruli, compared with normal-salt feeding, and these changes persisted 4 weeks after salt withdrawal. Tempol treatment (0.5 mmol/L) during high-salt feeding abolished the changes in DHE fluorescence, p22phox and SGK1. 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. Administration of tempol during high-salt feeding, or eplerenone, an MR antagonist (100 mg/kg/day), started after salt reduction, recovered proteinuria to normal levels at 4 weeks after salt reduction. Paraquat, a reactive oxygen species generator, enhanced MR transcriptional activity in cultured rat mesangial cells and mouse podocytes.ConclusionsThese results suggest that oxidative stress plays an important role in glomerular MR activation in Dahl salt-sensitive rats. Persistent MR activation even after reducing salt intake could limit the beneficial effects of salt restriction.
Highlights
Inappropriate regulation of the aldosterone/mineralocorticoid receptor (MR) system causes sodium retention and hypertension
These results suggest that oxidative stress plays an important role in glomerular Mineralocorticoid receptor (MR) activation in Dahl saltsensitive rats
Four-week high-salt feeding did not increase the levels of SGK1 and NHE1 mRNAs, transcriptional targets of MR [35,36,37], in whole kidney samples (Figure 1A and 1C), whereas significant increases in SGK1 and NHE1 mRNA levels were observed in laser-captured glomeruli from HS rats (Figure 1B and 1D)
Summary
Inappropriate regulation of the aldosterone/mineralocorticoid receptor (MR) system causes sodium retention and hypertension. MR antagonists have been shown to attenuate renal injury, especially glomerular injury, even under low circulating aldosterone levels, such as in salt-sensitive hypertension [11,12,13,14]. We previously reported that high-salt feeding decreased plasma aldosterone levels, increased the expression of MR target-gene expression in microdissected glomeruli, and induced glomerular injury and proteinuria in Dahl salt-sensitive (DS) rats [11]. This evidence suggests that the contribution of MR to renal injury cannot be estimated by plasma aldosterone levels. Mineralocorticoid receptor (MR) antagonists attenuate renal injury in salt-sensitive hypertensive rats with low plasma aldosterone levels. We determined if MR activation persisted and induced renal injury, even after switching from a high- to a normal-salt diet
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