Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats

Abstract

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, nϭ6); aldosterone (0.75 g/H, SC, nϭ8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, nϭ8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking solution, nϭ8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH 2 -terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot analysis. Aldosteroneinfused rats showed higher systolic blood pressure (165Ϯ5 mm Hg) and urinary excretion of protein (106Ϯ24 mg/d) than vehicle-infused rats (118Ϯ3 mm Hg and 10Ϯ3 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 (0.23Ϯ0.02) than vehicle-infused rats (0.09Ϯ0.01 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 (127Ϯ2 and 125Ϯ5 mm Hg), and the elevations of urinary excretion of protein (10Ϯ2 and 9Ϯ2 mg/day) or TBARS contents (0.08Ϯ0.01 and 0.11Ϯ0.01 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.

Total antioxidant status and oxidative DNA damage in a South Indian population of essential hypertensives

“…Vascular oxidative stress has also been demonstrated in experimentally induced hypertension, such as Ang II-mediated hypertension, Dahl salt-sensitive hypertension, lead-induced hypertension, obesity-associated hypertension, mineralocorticoid hypertension, and aldosterone-provoked hypertension. 31 In view of present data, it is seen that increased oxidative DNA damage and decreased serum TAS level were frequently observed in the newly diagnosed essential hypertensive patients, suggesting that oxidative stress is important in the pathogenesis of EH. Consequently, prevention of DNA damage may be inadequate in hypertensive patients with particularly newly diagnosed EH patients.…”

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…Active Heymann nephritis (AHN) is a model of human membranous nephropathy, and is associated with oxidantantioxidant imbalance, which contributes to renal damage [113]. Likewise, glomerular mesangial injury in rats treated chronically with aldosterone and salt is associated with induction of Nox2, Nox4 and p22 phox [114], increased p47 phox and p67 phox in the membrane fraction (indicating activation of the Nox2 system), and increased renal ROS and [102]. In an Angiotensin II-induced mesangioproliferative model of glomerulonephritis, Nox2 and Nox4 induction were associated with disease progression, and treatment with the antioxidant probucol in combination with Angiotensin II receptor blockade fully arrested disease progression and proteinuria [115].…”

Ginsenoside Rg1 protects mouse podocytes from aldosterone-induced injury in vitro

“…In addition to its hemodynamic effects, the local effects of aldosterone on renal cells, including proximal tubular cells, mesangial cells, and podocytes, are currently being studied, and accumulating evidence suggests that aldosterone plays a pathogenic role in renal injury, leading to severe proteinuria and glomerular injury [10] . Aldosterone-induced renal cell apoptosis is mediated by ROS [11,12] . In podocytes, the major sources of cellular ROS are the mitochondrial electron transport chain and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases.…”