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Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats.

Kitada K, Nakano D, Liu Y, Fujisawa Y, Hitomi H, Shibayama Y, Shibata H, Nagai Y, Mori H, Masaki T, Kobori H, Nishiyama A - PLoS ONE (2012)

Bottom Line: 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.Persistent MR activation even after reducing salt intake could limit the beneficial effects of salt restriction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.

ABSTRACT

Background: Mineralocorticoid 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 findings: High-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.

Conclusions: These 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.

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Related in: MedlinePlus

Effects of high-salt feeding and tempol treatment on expression of serum and glucocorticoid-regulated kinase (SGK)1 and Na+/H+ exchanger isoform (NHE)1 in whole kidney (A and C) and glomeruli (B and D) at 4 weeks after high-salt treatment.Data are expressed as means ± S.E.M.; n = 4 per group. *P<0.05, **P<0.01, compared to high-salt group.
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pone-0041896-g001: Effects of high-salt feeding and tempol treatment on expression of serum and glucocorticoid-regulated kinase (SGK)1 and Na+/H+ exchanger isoform (NHE)1 in whole kidney (A and C) and glomeruli (B and D) at 4 weeks after high-salt treatment.Data are expressed as means ± S.E.M.; n = 4 per group. *P<0.05, **P<0.01, compared to high-salt group.

Mentions: 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). The increases in glomerular SGK1 and NHE1 expression were markedly suppressed in the HS+tempol group, indicating that MR signaling was augmented in glomeruli in high-salt-fed DS rats, as reported previously [11]. We also reported previously that the increase in glomerular SGK1 expression in this model was prevented by eplerenone [11]. Renal oxidative stress was analyzed using three different methods. Urinary 8-OHdG excretion was markedly increased in HS rats after 4 weeks of high-salt feeding (Figure 2A). DHE fluorescence was also increased in both low-power-field kidney cross sections (2.0±0.1 fold vs. 1.0±0.2 fold in NS rats, P<0.01) and glomeruli (Figure 2B) in HS rats after 4 weeks of high-salt feeding. In addition, a high-salt diet increased mRNA expression of p22phox, a subunit of NADPH oxidase, in laser-captured glomeruli in HS rats (Figure 2C). Tempol treatment suppressed the increases in all three markers of oxidative stress (DHE fluorescence in low power field; 1.3±0.1 fold, P<0.01) in HS rats.


Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats.

Kitada K, Nakano D, Liu Y, Fujisawa Y, Hitomi H, Shibayama Y, Shibata H, Nagai Y, Mori H, Masaki T, Kobori H, Nishiyama A - PLoS ONE (2012)

Effects of high-salt feeding and tempol treatment on expression of serum and glucocorticoid-regulated kinase (SGK)1 and Na+/H+ exchanger isoform (NHE)1 in whole kidney (A and C) and glomeruli (B and D) at 4 weeks after high-salt treatment.Data are expressed as means ± S.E.M.; n = 4 per group. *P<0.05, **P<0.01, compared to high-salt group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404044&req=5

pone-0041896-g001: Effects of high-salt feeding and tempol treatment on expression of serum and glucocorticoid-regulated kinase (SGK)1 and Na+/H+ exchanger isoform (NHE)1 in whole kidney (A and C) and glomeruli (B and D) at 4 weeks after high-salt treatment.Data are expressed as means ± S.E.M.; n = 4 per group. *P<0.05, **P<0.01, compared to high-salt group.
Mentions: 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). The increases in glomerular SGK1 and NHE1 expression were markedly suppressed in the HS+tempol group, indicating that MR signaling was augmented in glomeruli in high-salt-fed DS rats, as reported previously [11]. We also reported previously that the increase in glomerular SGK1 expression in this model was prevented by eplerenone [11]. Renal oxidative stress was analyzed using three different methods. Urinary 8-OHdG excretion was markedly increased in HS rats after 4 weeks of high-salt feeding (Figure 2A). DHE fluorescence was also increased in both low-power-field kidney cross sections (2.0±0.1 fold vs. 1.0±0.2 fold in NS rats, P<0.01) and glomeruli (Figure 2B) in HS rats after 4 weeks of high-salt feeding. In addition, a high-salt diet increased mRNA expression of p22phox, a subunit of NADPH oxidase, in laser-captured glomeruli in HS rats (Figure 2C). Tempol treatment suppressed the increases in all three markers of oxidative stress (DHE fluorescence in low power field; 1.3±0.1 fold, P<0.01) in HS rats.

Bottom Line: 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.Persistent MR activation even after reducing salt intake could limit the beneficial effects of salt restriction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.

ABSTRACT

Background: Mineralocorticoid 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 findings: High-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.

Conclusions: These 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.

Show MeSH
Related in: MedlinePlus