MECHANISMS UNDERLYING THE RENAL TOXICITY INDUCED BY CHRONIC ETHANOL CONSUMPTION: THE ROLE OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS)

Abstract

Despite the fact that consumption of ethyl alcohol (ethanol) is legal and encouraged by society, long-term ethanol intake induces many physiological changes in different tissues, including the kidney. Chronic ethanol consumption, by mechanisms that are unknown, is associated to increase renal nitric oxide (NO) production. The latter is a free radical that plays a role in distinct physiological functions, but in high concentrations contributes to the pathophysiology of kidney diseases such as acute renal failure, glomerulonephritis and diabetic nephropathy. The expression of the inducible isoform of NO sinthase (iNOS) is induced by ethanol in several tissues. In renal disease, iNOS is the major enzyme producing NO. In addition to the iNOS induction, ethanol consumption increases reactive oxygen species (ROS) generation. This process is mediated by the enzyme NAD(P)H oxidase which produces superoxide anion (O2-). The reaction between NO and O2- leads to the generation of peroxynitrite (ONOO-) , which is a powerful oxidizing agent that participates in nephropathy process. ONOO- induces structural and functional changes in the glomerulus and generates multiple abnormalities of renal tubule leading to widespread tubular dysfunction and renal disorders, which affect electrolyte content and extracellular volume regulation and acid-base balance. Ethanol consumption is also described to induce hypomagneseamia, acute tubular necrosis and mitochondrial dysfunction. Although ethanol consumption is described as a risk factor for the development of renal dysfunction, it is still unclear the mechanisms involved in this response. Our hypothesis is that chronic ethanol consumption induces iNOS expression in the kidney and increases renal ROS production via NAD(P)H oxidase. This process would lead to increased ONOO- formation with consequent renal dysfunction. Thus, the purpose of this study is assess the role of iNOS on the renal toxicity induced by chronic ethanol consumption.