LPS DECREASES CFTR OPEN PROBABILITY AND MUCOCILIARY TRANSPORT THROUGH GENERATION OF REACTIVE OXYGEN SPECIES

The use of cyclosporine A (CsA) in transplant recipients is limited due to its side effects of causing severe hypertension. We have previously shown that CsA increases the activity of the epithelial sodium channel (ENaC) in cultured distal nephron cells. However, it remains unknown whether ENaC mediates CsA-induced hypertension and how we could prevent hypertension. Our data show that the open probability of ENaC in principal cells of split-open cortical collecting ducts was significantly increased after treatment of rats with CsA; the increase was attenuated by lovastatin. Moreover, CsA also elevated the levels of intracellular cholesterol (Cho), intracellular reactive oxygen species (ROS) via activation of NADPH oxidase p47phox, serum- and glucocorticoid-induced kinase isoform 1 (Sgk1), and phosphorylated neural precursor cell–expressed developmentally downregulated protein 4–2 (p-Nedd4-2) in the kidney cortex. Lovastatin also abolished CsA-induced elevation of α-, ß-, and γ-ENaC expressions. CsA elevated systolic blood pressure in rats; the elevation was completely reversed by lovastatin (an inhibitor of cholesterol synthesis), NaHS (a donor of H2S which ameliorated CsA-induced elevation of reactive oxygen species), or amiloride (a potent ENaC blocker). These results suggest that CsA elevates blood pressure by increasing ENaC activity via a signaling cascade associated with elevation of intracellular ROS, activation of Sgk1, and inactivation of Nedd4-2 in an intracellular cholesterol-dependent manner. Our data also show that NaHS ameliorates CsA-induced hypertension by inhibition of oxidative stress.

Download Full-text

Ethanol stimulates epithelial sodium channels by elevating reactive oxygen species

AJP Cell Physiology ◽

10.1152/ajpcell.00139.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. C1129-C1138 ◽

Cited By ~ 14

Author(s):

Hui-Fang Bao ◽

John Z. Song ◽

Billie J. Duke ◽

He-Ping Ma ◽

Donald D. Denson ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Sodium Channels ◽

Single Channel ◽

Reactive Oxygen ◽

Metabolic Product ◽

Sodium Balance ◽

Oxygen Species ◽

Epithelial Sodium Channels ◽

Open Probability ◽

Intracellular Ros

Alcohol affects total body sodium balance, but the molecular mechanism of its effect remains unclear. We used single-channel methods to examine how ethanol affects epithelial sodium channels (ENaC) in A6 distal nephron cells. The data showed that ethanol significantly increased both ENaC open probability ( Po) and the number of active ENaC in patches ( N). 1-Propanol and 1-butanol also increased ENaC activity, but iso-alcohols did not. The effects of ethanol were mimicked by acetaldehyde, the first metabolic product of ethanol, but not by acetone, the metabolic product of 2-propanol. Besides increasing open probability and apparent density of active channels, confocal microscopy and surface biotinylation showed that ethanol significantly increased α-ENaC protein in the apical membrane. The effects of ethanol on ENaC Po and N were abolished by a superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) and blocked by the phosphatidylinositol 3-kinase inhibitor LY294002. Consistent with an effect of ethanol-induced reactive oxygen species (ROS) on ENaC, primary alcohols and acetaldehyde elevated intracellular ROS, but secondary alcohols did not. Taken together with our previous finding that ROS stimulate ENaC, the current results suggest that ethanol stimulates ENaC by elevating intracellular ROS probably via its metabolic product acetaldehyde.

Download Full-text

Mitochondria as a source of reactive oxygen species

Biochemical Journal ◽

10.1042/bj20090056 ◽

2009 ◽

pp. c3 ◽

Cited By ~ 1

Author(s):

Helena M. Cochemé ◽

Michael P. Murphy

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species

Download Full-text

Clinical aspects of reactive oxygen and nitrogen species

Biochemical Society Symposium ◽

10.1042/bss0710121 ◽

2004 ◽

Vol 71 ◽

pp. 121-133 ◽

Cited By ~ 25

Author(s):

Ascan Warnholtz ◽

Maria Wendt ◽

Michael August ◽

Thomas Münzel

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Risk Factor ◽

Endothelial Dysfunction ◽

Vascular Tissue ◽

Rapid Development ◽

Reactive Oxygen ◽

Clinical Aspects ◽

No Production ◽

Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

Download Full-text