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

PLoS One. 2012;7(7):e41896. doi: 10.1371/journal.pone.0041896. Epub 2012 Jul 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenalectomy
  • Aldosterone / blood
  • Animals
  • Biomarkers / metabolism
  • Blood Pressure / drug effects
  • Cyclic N-Oxides / pharmacology
  • Ethidium / analogs & derivatives
  • Ethidium / metabolism
  • Feeding Behavior / drug effects
  • Genes, Reporter
  • Immediate-Early Proteins / metabolism
  • Kidney Glomerulus / enzymology
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology*
  • Kidney Glomerulus / physiopathology
  • Luciferases / metabolism
  • Male
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism
  • Mice
  • Oxidative Stress / drug effects*
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteinuria / blood
  • Proteinuria / pathology
  • Proteinuria / physiopathology
  • Rats
  • Rats, Inbred Dahl
  • Receptors, Mineralocorticoid / metabolism*
  • Sodium Chloride, Dietary / administration & dosage
  • Sodium Chloride, Dietary / pharmacology*
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / metabolism
  • Spin Labels
  • Systole / drug effects
  • Time Factors

Substances

  • Biomarkers
  • Cyclic N-Oxides
  • Immediate-Early Proteins
  • Receptors, Mineralocorticoid
  • Slc9a1 protein, rat
  • Sodium Chloride, Dietary
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • Spin Labels
  • dihydroethidium
  • Aldosterone
  • Luciferases
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Ethidium
  • tempol