Effects of Exercise Training on Mitochondrial Fatty Acid ß-Oxidation in the Kidneys of Dahl Salt-Sensitive Rats.

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16-20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of ß-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of ß-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid ß-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney.

Exercise Training Prevents High Fructose-Induced Hypertension and Renal Damages in Male Dahl Salt-Sensitive Rats.

INTRODUCTION: High-fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) has antihypertensive and renal protective effects in rats fed HFr; however, there has been little discussion about the DS rats, which exhibit metabolic disturbances. This study thus examined the effects of Ex on DS rats fed HFr. METHODS: Male DS rats were divided into three groups. The control group was fed a control diet, and both the HFr group and the HFr-Ex group were fed an HFr (60% fructose). The HFr-Ex group also underwent treadmill running (20 m·min -1 , 60 min·d -1 , 5 d·wk -1 ). After 12 wk, renal function, histology, and renin-angiotensin system were examined. RESULTS: HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor, and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type 2 receptor, and Mas receptor, and Ex restored the ACE2 and Mas receptor expressions to the control levels and further decreased the angiotensin II type 2 receptor expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. CONCLUSIONS: Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal renin-angiotensin system may be involved in the mechanism of the antihypertensive and renal protective effects of Ex.

Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats.

OBJECTIVE: Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats. METHODS: Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks. RESULTS: Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks. CONCLUSION: Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.

Effects of Exercise Training on the Renin-Angiotensin System in the Kidneys of Dahl Salt-Sensitive Rats.

PURPOSE: Exercise training (Ex) has antihypertensive and renal protective effects; however, the precise mechanisms remain unclear. The renal renin-angiotensin system (RAS) plays a vital role in renal function and pathology. Therefore, we investigated the effects of Ex on the renal RAS components in Dahl salt-sensitive (Dahl-S) rats. METHODS: Male Dahl-S rats were divided into four groups: normal salt diet + sedentary, normal salt diet + Ex, high-salt diet (HS, 8% NaCl) + sedentary, and HS + Ex. Treadmill running was performed for 8 wk in the Ex groups. RESULTS: Ex attenuated the HS-induced renal dysfunction and glomerular injury without causing blood pressure alterations. HS increased urinary excretion of both total and intact angiotensinogen. Ex decreased the HS-induced increased urinary excretion of total angiotensinogen. However, it did not change the HS-induced urinary excretion of intact angiotensinogen, indicating reduced intact angiotensinogen cleaving. Ex restored the HS-induced increased angiotensinogen and angiotensin II type 1 receptor expressions in the outer medulla and the HS-induced increased angiotensin-converting enzyme expression in the cortex. Ex restored the HS-induced decreased renin expression in the cortex and outer medulla, and the HS-induced decreased angiotensin-converting enzyme 2, angiotensin II type 2 receptor, and Mas receptor expressions in the outer medulla. CONCLUSIONS: Ex attenuates HS-induced renal dysfunction, glomerular injury, and renal RAS dysregulation in Dahl-S rats.

Xanthine Oxidase Inhibitor, Febuxostat Ameliorates the High Salt Intake-Induced Cardiac Hypertrophy and Fibrosis in Dahl Salt-Sensitive Rats.

BACKGROUND: Xanthine oxidase (XO) is a source of reactive oxygen species production in the heart. However, pathophysiological role of XO has not been clarified in hypertensive heart disease. Thus, the present study examined the impacts of high salt (HS) intake and febuxostat (Fx), a XO inhibitor in Dahl salt-sensitive (Dahl-S) rats. METHODS: Eight-week old, male Dahl-S rats were fed a normal salt diet (0.6% NaCl) or a HS diet (8% NaCl) for 8 weeks. A part of the rats fed the HS diet were simultaneously treated with Fx (3 mg/kg/day). RESULTS: HS intake increased blood pressure and heart weight with cardiomyocyte hypertrophy and interstitial fibrosis in the left ventricle (LV), and Fx diminished them. HS increased the XO activity 4.7-fold and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity 1.5-fold, and Fx not only blocked the XO activity but also inhibited the HS-increased NADPH oxidase activity. HS increased the expression of XO, collagen, transforming growth factor-ß1 (TGF-ß1), angiotensin-converting enzyme, and angiotensin II type 1 receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the LV, and Fx reduced the expression and phosphorylation of these proteins except XO. CONCLUSIONS: Fx ameliorates the HS intake-induced hypertension, LV hypertrophy, and fibrosis with decreasing the TGF-ß1 expression and ERK phosphorylation in Dahl-S rats. Fx also down-regulates cardiac NADPH oxidase and renin-angiotensin system. The XO inhibition may be an effective therapy for hypertensive heart disease.