Abstract-The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (nϭ60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158Ϯ3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8Ϯ3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid-reactive substances showed a significant increase in the LDL fraction of OP rats (2.8Ϯ0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9Ϯ0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid-reactive substances showed a significant (3-and 5-fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptasepolymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/␤-actin ratio 1.3Ϯ0.04 in OP rats versus 0.44Ϯ0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress. Key Words: diet Ⅲ nitric oxide Ⅲ obesity Ⅲ oxidative stress Ⅲ kidney Ⅲ lipids O besity is an important contributor to essential hypertension in humans. Data from the Framingham Heart Study suggest that Ϸ78% of essential hypertension in men and Ϸ65% in women can be directly attributed to obesity. 1 However, the mechanisms that link obesity with high blood pressure (BP) have not been fully elucidated. There are data that indicate increased oxidative stress in human essential hypertension 2,3 as well as in obese hypertensive patients. 4 Also, the involvement of the superoxide radical in BP regulation has been reported for several animal models of hypertension, such as the spontaneously hypertensive rat, 5,6 Dahl rat, 7 and angiotensin II-infused rat. 8 Romero's group (Haas et al 9 and Reckelhoff et al 10 ) has recently reported that subpressor doses of angiotensin II are able to generate oxidative stress in pigs and rats, which, in turn, is able to induce chronic elevations in BP. The increase in superoxide production in hypertension has been shown to have an impact ...

Abstract-The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (nϭ6 per group). At the end of the diet, peroxisome proliferator activated receptor-␥ (PPAR␥) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPAR␥ expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BPϭ159Ϯ5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BPϭ123.9Ϯ2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability. Key Words: kidney Ⅲ oxidative stress Ⅲ free radicals Ⅲ nitric oxide Ⅲ vitamins O besity is a widespread and increasingly prevalent condition associated with a large number of comorbid diseases, one of the most important of which is obesityinduced hypertension. A pleiotropic class of molecules involved in regulation of gene expression in a variety of metabolic and cardiovascular conditions is the peroxisome proliferator-activated receptors (PPARs). PPARs are ligandactivated transcription factors that form heterodimers with the 9-cis retinoic acid receptor RXR␣. 1 PPAR␥ is one of the three PPAR isoforms and is one of the major regulators of adipogenesis. 2 In addition, PPAR␥ exerts pleiotropic effects on blood pressure, lipid metabolism, and insulin action.Recent genetic analysis showed that 2 dominant-negative mutations in PPAR␥ were associated with severe hypertension in humans. 3,4 Consistent with these findings, thiazolidinendiones, the insulin-sensitizer drugs (pioglitazone, rosiglitazone) that are also high-affinity PPAR␥ ligands, 5 have been shown to lower blood pressure (BP) in a variety of hypertensive animal models 6 -8 as well as in diabetic and nondiabetic, 9 hypertensive humans. However, the mechanism underlying the antihypertensive effects of PPAR␥ agonists is not known. PPAR␥ and RXR have been found constitutively expressed in the inner medullary collecting ducts, thick ascending limb, glomerulus, and renal medullary mic...

. Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity. Am J Physiol Renal Physiol 285: F619-F628, 2003. First published June 10, 2003 10.1152 10. /ajprenal.00388. 2002 diet is known to induce or aggravate hypertension in animal models of hypertension and in humans. When Sprague-Dawley rats (n ϭ 60) are fed a moderately high-fat diet (32% kcal fat, 0.8% NaCl) for 10 wk, about one-half develop obesity [obesity prone (OP)] and mild hypertension, whereas the other half [obesity resistant (OR)] maintain body weight equivalent to a low-fat control (C) and are normotensive. The aim of this study was to test the effect of high-NaCl diets (2 and 4% NaCl) on the development of hypertension and obesity, oxidative stress, and renal function. Both 2 and 4% NaCl induced an early increase in systolic blood pressure of OP but not OR or C rats. High-salt intake induced an increase in the size and reduction in number of adipocytes, concomitant to a twofold increase in circulating leptin in OP rats. Aortic superoxide generation indicated a 2.8-fold increase in the OP high-salt vs. normalsalt groups, whereas urine isoprostanes were not significantly increased. Also, hydroxynonenal protein adducts in the kidney were highly increased in OP rats on 2 and 4% NaCl, indicating oxidative stress in the renal tissue. Urine albumin was increased threefold in the OP on 2% NaCl and fourfold in the same group on 4% NaCl vs. 0.8% NaCl. Kidney histology indicated a higher degree of glomerulosclerosis in OP rats on high-salt diets. In summary, high-salt diet accelerated the development but did not increase the severity of hypertension; high salt increased oxidative stress in the vasculature and kidney and induced kidney glomerulosclerosis and microalbuminuria. Also, the OP rats on high salt displayed adipocyte hypertrophy and increased leptin production.glomerulosclerosis; kidney; leptin; sodium dietary OBESITY IS A complex, multifactorial disease that is associated with essential hypertension in ϳ78% of men and ϳ65% of women, as indicated by the data from the Framingham Heart Study (25). Another important contributor to hypertension in humans is the excessive consumption of dietary salt, and epidemiological studies have demonstrated a significant but weak relation between salt intake and hypertension (32, 33). Some, but not all, interventional studies have shown that salt restriction may lower blood pressure (BP) (19,33). Some recent studies report correlation among hypertension, salt sensitivity, and insulin resistance in obese humans (38), whereas others fail to observe a significant relationship (8). Animal models of obesity, hypertension, and insulin resistance display differences with respect to salt sensitivity. In Zucker rats, there is a clear correlation between salt intake and the severity of hypertension (4, 47), whereas in chronic hyperinsulinemic Sprague-Dawley (SD) rats, hypertension is not salt sensitive, albeit a shift in pressure-natriuresis relationship was reported (2). One important cont...

Abstract-One-kidney, 1-clip rats (1K1C) or uninephrectomized controls were treated with either the superoxide dismutase mimetic tempol (0.5 mmol · kg Ϫ1 · d Ϫ1 ), angiotension type 1 receptor inhibitor losartan (50 mmol · L Ϫ1 · kg Ϫ1 · d Ϫ1 ), or both (nϭ6 per group) for 2 weeks. At the end of the study, systolic blood pressure (BP) decreased on average by 21% in tempol-treated and 29% in losartan-treated versus untreated 1K1C (217Ϯ4.4 mm Hg) and was normalized in the losartan plus tempol group. Mean BP also decreased from 159Ϯ3.7 mm Hg in 1K1C to 93Ϯ2.8 mm Hg in the losartan plus tempol group. Also, aortic wall area was reduced by 18% in losartan-or tempol-treated 1K1C and by 30% in losartan plus tempol rats compared with untreated 1K1C. Plasma renin activity was increased from 4.8Ϯ0.3 in untreated 1K1C to 15.9Ϯ0.9 ng · mL Ϫ1 · h Ϫ1 in losartan-treated but not tempol-treated 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin chemiluminescence was significantly decreased (by Ϸ40%) in all losartan, tempol, and losartan plus tempol groups compared with untreated 1K1C. Nitrotyrosine ELISA in the kidney displayed a significant reduction, from 59Ϯ13 ng/mg of protein in 1K1C to 12.5Ϯ5 ng/mg of protein in the losartan plus tempol 1K1C. Western blotting for nNOS in kidney cortex and medulla showed a protein increase in both fractions of 1K1C versus controls and was normalized by losartan plus tempol treatment. Collectively, data show a synergistic effect of losartan and tempol on BP reduction in 1K1C rats. The mechanism may involve reduced superoxide production and nitrotyrosine formation in kidney and decreased kidney neuronal-type NO synthase expression in treated animals. This status in the oxidative balance seems to affect BP in the renal hypertensive rats. Key Words: superoxide Ⅲ nitric oxide Ⅲ nitrotyrosine Ⅲ losartan Ⅲ tempol Ⅲ kidney Ⅲ aorta I nvolvement of oxidative stress in the pathology of hypertension was reported recently for humans with essential hypertension, 1,2 preeclamptic human women, 3 and animal models such as the spontaneously hypertensive, 4,5 Dahl saltsensitive, 6,7 or angiotensin (Ang) II-infused rat. 8 In addition, an important role of free radicals in blood pressure (BP) regulation was shown in a model of lead-induced hypertension, 9 in chronic renal failure 10 and in a model of diet-induced hypertension in rat. 11 Moreover, a direct role of oxidative stress in inducing hypertension was shown by Vaziri et al 12 in intact genetically normotensive rats that were made hypertensive by direct induction of oxidative stress via in vivo glutathione depletion. The main free radical that seems to be involved in the pathology of different forms of hypertension is the superoxide anion. This can either act as a vasoconstrictor 13,14 or, under certain circumstances, can interact rapidly with NO 15 to reduce its bioavailability and further increase vasoconstriction. 16,17 Furthermore, peroxynitrite formed after interaction of superoxide with NO is a more potent oxidant that can ...

Abstract-Elevated blood pressure is associated with varying degrees of arterial growth and remodeling. The mechanisms by which mechanical stress is converted into cellular alteration have yet to be fully elucidated. Our laboratory has demonstrated that Src tyrosine kinases and the extracellular signal-regulated kinase subtype of the mitogen-activated protein kinase family mediate pressure-induced c-fos expression in rat mesenteric arteries. Others have reported involvement of integrin and growth factor receptor signaling pathways. Our goal was to determine the role of Src, focal adhesion kinase (FAK), and platelet-derived growth factor (PDGF) receptor signaling in the upstream initiation of these events. Pairs of rat mesenteric arteries were pressurized to 90 mm Hg (control), and then one was raised to 140 mm Hg for 1, 3, or 5 minutes. Western blotting revealed that Src-pY 418 was elevated 2.4-fold over control values at 1 minute and 2.8-fold at 3 minutes and returned to control at 5 minutes. Significant FAK-Y 397 phosphorylation was observed only after 3 and 5 minutes of pressure stimulus and was blocked entirely by Src inhibition. Src-pY 215 activity (associated with PDGF receptor activation) does not seem to be involved at any of the time points tested. These data demonstrate that Src-Y 418 autophosphorylation is an early event in pressure mechanotransduction and leads to activation of FAK-Y 397 . This finding suggests that Src may be the messenger that initiates and propagates the cellular growth response to pressure stimulus, and FAK is one of its downstream targets. Src phosphorylation due to PDGF receptor activation does not seem to be involved in the initial response. Key Words: hypertension, chronic Ⅲ signal transduction Ⅲ arteries Ⅲ remodeling Ⅲ kinase Ⅲ platelet-derived growth factor C hronic hypertension is associated with varying degrees of hypertrophic and eutrophic arterial remodeling. Arterioles, or "resistance vessels," possess an intrinsic ability to develop myogenic tone and initially vasoconstrict in an attempt to counteract an increase in wall stress due to elevated pressure. 1 Over time, the sustained vasoconstriction will prompt a more permanent structural reduction in lumen diameter through inward eutrophic remodeling. 2 The larger arteries, or "conducting vessels," lack myogenic tone and eventually undergo outward hypertrophy to "tolerate" or counteract the increase in wall stress. Small arteries possess intermediate characteristics and demonstrate both inward and outward hypertrophy. 3,4 Our current hypothesis is that wall stress governs this vascular response. 5 However, the mechanisms by which extracellular mechanical stress is converted into intracellular alterations in signal transduction and gene expression have yet to be fully elucidated.Cells detect and transmit sensory data from their environment in a variety of ways. In the case of hypertension, cell surface receptors or associated molecules may be the sensors that perceive changes in extracellular forces and act as molecular s...