Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension

Abstract

Knight SF, Yuan J, Roy S, Imig JD. Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension. Am J Physiol Renal Physiol 298: F86 -F94, 2010. First published November 11, 2009 doi:10.1152/ajprenal.00351.2009.-Obesity and hypertension are risk factors for the development of chronic kidney disease. The mechanisms by which elevated blood pressure and fatty acids lead to the development of renal injury are incompletely understood. Here, we investigated the contributions of cholesterol and oxidative stress to renal endothelial dysfunction and glomerular injury in a model of obesity and hypertension. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were fed a normal diet, a high-fat diet, a high-fat diet with tempol, or a high-fat diet with simvastatin for up to 10 wk. Blood pressure was not altered by a high-fat diet or treatments. After 3 wk, renal afferent dilatory responses to acetylcholine were impaired in WKY rats and SHR fed a high-fat diet. Tempol treatment prevented this vascular dysfunction in both strains; however, simvastatin treatment demonstrated greater beneficial effects in the SHR. Albuminuria was observed in the SHR and was exacerbated by a high-fat diet. Tempol and simvastatin treatment significantly ameliorated albuminuria in the SHR fed a high-fat diet. Ten weeks on a high-fat resulted in an increase in urinary 8-isoprostane in WKY rats and SHR, and tempol and simvastatin treatment prevented this increase, indicating a reduction in renal oxidative stress. Monocyte chemoattractant protein-1 (MCP-1) excretion was significantly elevated by a high-fat diet in both strains, and tempol prevented this increase. Interestingly, simvastatin treatment had no effect on MCP-1 levels. These data indicate that tempol and simvastatin treatment via a reduction in oxidative stress improve renal endothelial function and decrease glomerular injury in a model of obesity and hypertension. kidney; oxidative stress; metabolic syndrome; inflammation OBESITY HAS REACHED EPIDEMIC proportions in the developed world, with 50% of the US population now classified as overweight or obese, and the numbers are rising (National Health and Nutrition Examination Survey, available at http:// www.cdc.gov/nchs/nhanes.htm). Obesity is associated with increased risk of developing diabetes, hypercholesterolemia, and hypertension, which together are described as the metabolic syndrome (18, 29). Independently, obesity and hypertension increase the risk of renal dysfunction; obese patients are four times more likely to develop renal disease than nonobese patients, and hypertension accounts for 25% of renal dysfunction cases (27). Obese patients are at a higher risk of developing hypertension, therefore combining risk factors and compounding the negative effect on cardiovascular health. In particular, renal injury associated with obesity and hypertension has been shown to be more severe than renal disease observed as a result of each risk factor alone. This addi...

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