Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats

Hypertension. 2004 Apr;43(4):841-8. doi: 10.1161/01.HYP.0000118519.66430.22. Epub 2004 Feb 9.

Abstract

Studies were performed to test the hypothesis that reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) contribute to the pathogenesis of aldosterone/salt-induced renal injury. Rats were given 1% NaCl to drink and were treated with one of the following combinations for 6 weeks: vehicle (0.5% ethanol, SC, n=6); aldosterone (0.75 microg/H, SC, n=8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, n=8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking solution, n=8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH2-terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot analysis. Aldosterone-infused rats showed higher systolic blood pressure (165+/-5 mm Hg) and urinary excretion of protein (106+/-24 mg/d) than vehicle-infused rats (118+/-3 mm Hg and 10+/-3 mg/d). Renal cortical mRNA expression of p22phox, Nox-4, and gp91phox, measured by real-time polymerase chain reaction, was increased in aldosterone-infused rats by 2.3, 4.3, and 3.0-fold, respectively. Thiobarbituric acid-reactive substances (TBARS) content in renal cortex was also higher in aldosterone (0.23+/-0.02) than vehicle-infused rats (0.09+/-0.01 nmol/mg protein). ERK1/2, JNK, and BMK1 activities were significantly elevated in aldosterone-infused rats by 3.3, 2.3, and 3.0-fold, respectively, whereas p38MAPK activity was not changed. Concurrent administration of eplerenone or tempol to aldosterone-infused rats prevented the development of hypertension (127+/-2 and 125+/-5 mm Hg), and the elevations of urinary excretion of protein (10+/-2 and 9+/-2 mg/day) or TBARS contents (0.08+/-0.01 and 0.11+/-0.01 nmol/mg protein). Furthermore, eplerenone and tempol treatments normalized the activities of ERK1/2, JNK, and BMK1. These data suggest that ROS and MAPK play a role in the progression of renal injury induced by chronic elevations in aldosterone.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / toxicity*
  • Animals
  • Cyclic N-Oxides / pharmacology
  • Cyclic N-Oxides / therapeutic use
  • Eplerenone
  • Hypertension / chemically induced*
  • Hypertension / metabolism
  • Hypertension / pathology
  • JNK Mitogen-Activated Protein Kinases
  • Kidney Cortex / drug effects
  • Kidney Cortex / metabolism*
  • Kidney Cortex / pathology
  • MAP Kinase Signaling System
  • Male
  • Membrane Transport Proteins / biosynthesis
  • Membrane Transport Proteins / genetics
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases / physiology*
  • NADPH Dehydrogenase / biosynthesis
  • NADPH Dehydrogenase / genetics
  • NADPH Oxidase 4
  • NADPH Oxidases / biosynthesis
  • NADPH Oxidases / genetics
  • Oxidative Stress
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Proteinuria / chemically induced
  • Proteinuria / metabolism
  • Proteinuria / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*
  • Sodium Chloride / toxicity*
  • Spin Labels
  • Spironolactone / analogs & derivatives*
  • Spironolactone / pharmacology

Substances

  • Cyclic N-Oxides
  • Membrane Transport Proteins
  • Phosphoproteins
  • Reactive Oxygen Species
  • Spin Labels
  • Spironolactone
  • Sodium Chloride
  • Aldosterone
  • Eplerenone
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, rat
  • CYBA protein, human
  • NADPH Dehydrogenase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases
  • tempol