Article

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

Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA.
AJP Renal Physiology (Impact Factor: 4.42). 11/2009; 298(1):F86-94.
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
41 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied. In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis. Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone. Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization.
    PLoS ONE 12/2014; 9(12):e115715. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Different modes of exercise are reported to be beneficial in subjects with chronic kidney disease (CKD). Similar benefits have also been ascribed to the dietary supplement gum acacia (GA). Using several physiological, biochemical, immunological, and histopathological measurements, we assessed the effect of swimming exercise (SE) on adenine -induced CKD, and tested whether SE would influence the salutary action of GA in rats with CKD. Eight groups of rats were used, the first four of which were fed normal chow for 5 weeks, feed mixed with adenine (0.25% w/w) to induce CKD, GA in the drinking water (15% w/v), or were given adenine plus GA, as above. Another four groups were similarly treated, but were subjected to SE during the experimental period, while the first four groups remained sedentary. The pre-SE program lasted for four days (before the start of the experimental treatments), during which the rats were made to swim for 5 to 10 min, and then gradually extended to 20 min per day. Thereafter, the rats in the 5th, 6th, 7th, and 8th groups started to receive their respective treatments, and were subjected to SE three days a week for 45 min each. Adenine induced the typical signs of CKD as confirmed by histopathology, and the other measurements, and GA significantly ameliorated all these signs. SE did not affect the salutary action of GA on renal histology, but it partially improved some of the above biochemical and physiological analytes, suggesting that addition of this mode of exercise to GA supplementation may improve further the benefits of GA supplementation.
    PLoS ONE 07/2014; 9(7):e102528. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage.
    Cancer Letters 07/2014; · 5.02 Impact Factor