Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo

Barton, Matthias; Carmona, Renata; Morawietz, Henning; d’Uscio, Livius V.; Göettsch, Winfried; Hillen, Heinz; Haudenschild, Christian C.; Krieger, José Eduardo; Münter, Klaus; Lattmann, Thomas; Lüscher, Thomas F.; Shaw, Sidney

doi:10.1161/01.hyp.35.1.329

Cited by 116 publications

(115 citation statements)

References 54 publications

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“…Indeed, Nielsen et al 27 showed a significant correlation between the vascular response to Ang II and the plasma palmitate concentration. In terms of Ang II-forming activity from Ang I, Barton et al 28 showed the activation of renal Ang-converting enzyme activity in obese animals. Increased FFA levels, however, did not alter the FBF response to either Ang I or II in the present study.…”

Section: Discussionmentioning

confidence: 99%

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

et al. 2010

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Abstract-Release of free fatty acid (FFA) from adipose tissue is implicated in insulin resistance and endothelial dysfunction in patients with visceral fat obesity. We demonstrated previously that increased FFA levels cause endothelial dysfunction that is prevented by inhibition of the renin-angiotensin system (RAS) in humans. However, the mechanisms for FFA-mediated activation of RAS and the resultant endothelial dysfunction were not elucidated. We investigated effects of elevated FFA on activity of circulating and vascular RAS, angiotensin II-forming activity of leukocytes, and leukocyte activation of normotensive subjects. We showed that increased FFA levels significantly enhanced angiotensin II-forming activity in human mononuclear (mean fold increase: 3.5 at 180 minutes; Pϭ0.0016) and polymorphonuclear (2.0; Pϭ0.0012) cells, whereas parameters of the circulating and vascular RAS were not affected. We also showed that FFA caused angiotensin II-dependent leukocyte activation, which impaired endothelial function partly via increased myeloperoxidase release and presumably enhanced adhesion of leukocytes. We propose that the enhanced production of angiotensin II by FFA in mononuclear and polymorphonuclear cells causes activation of leukocytes that consequently impairs endothelial function. RAS in leukocytes may regulate the leukocyte-vasculature interaction as the mobile RAS in humans. T he levels of circulating free fatty acid (FFA), mainly originating from lipolysis in adipose tissue, are increased in patients with metabolic syndrome and type 2 diabetes mellitus, 1-3 reflecting resistance to the antilipolytic action of insulin. Increased plasma FFA concentrations cause endothelial dysfunction, 4 insulin resistance, 5 and endothelial apoptosis. 6 These observations, together with results from epidemiological studies, 7,8 suggest that FFA is involved in atherosclerosis in subjects with insulin resistance. Recently, we have found that FFA-induced endothelial dysfunction is prevented by the inhibition of the renin-angiotensin (Ang) system (RAS) in humans, 9 suggesting that RAS activation by FFA may predominantly contribute to FFA-induced endothelial dysfunction. This hypothesis appears plausible because of the close relationship between obesity and RAS activity in humans. 10,11 In addition, RAS activation is also associated with enhanced oxidative stress, 12 which is an intermediary mechanism by which FFA adversely alters vascular function. 13 However, although the proatherogenic action of excessive Ang II has been well documented, there is little information regarding the mechanism of RAS activation in individuals with obesity. Indeed, only a few studies have investigated the effects of elevated FFA on RAS activity. 14 The aim of the present study was to investigate effects of elevated FFA on RAS and to elucidate mechanisms for FFA-induced endothelial dysfunction in humans. We also investigated the interaction between FFA and leukocytes, because FFA is involved in leukocyte activation through protein kinase C re...

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Section: Discussionmentioning

confidence: 99%

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

et al. 2010

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“…Importantly, obesity potentiated angiotensin II-induced vasoconstriction in aortic but not in carotid arterial rings in vitro, indicating that the vascular effects of angiotensin II are site specific in this model of experimental obesity [Barton et al, 2000].…”

Section: Obesity-related Sympathetic Activation and Vascular Remodelingmentioning

confidence: 83%

“…In addition, Nielsen et al [2004] studied obese subjects with family history of hypertension, which could per se potentiate the vasoconstrictor effect of angiotensin II. Furthermore, diverse vascular beds may respond differently to angiotensin II stimulation, as demonstrated in experimental models of obesity [Barton et al, 2000].…”

Section: Obesity-related Sympathetic Activation and Vascular Remodelingmentioning

confidence: 99%

Sympathetic Vascular Tone in Human Obesity

Agapitov

Sinkey

Dopp

et al. 2004

Journal of Hypertension

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Obesity is associated with increased sympathoactivation that elevates arterial pressure. However, the mechanism linking sympathetic activation to arterial pressure is unclear. Specifically, it has never been demonstrated unequivocally that sympathetically mediated vasoconstriction is increased in obesity. This project tested the hypothesis that sympathetic vascular tone is increased in obese normotensive and hypertensive subjects.The effect of weight loss on sympathetic vascular tone was also assessed.Sympathetic vascular tone was assessed as forearm vasodilatation to intra-arterial phentolamine (α 1/2 -adrenergic receptor antagonist). Pharmacological responses were correlated with skeletal muscle sympathetic nerve activity (mSNA). Obese subjects with and without hypertension had increased mSNA. However, the vasodilatator response to phentolamine was not augmented in obese normotensive and hypertensive subjects versus lean controls. Additionally, weight loss did not alter phentolamine's vasodilatator response, despite reducing mSNA and arterial pressure in obese groups. These results indicate that sympathetic vascular tone is not increased in obesity despite higher mSNA.These studies also assessed forearm resistance vessel function using intra-arterial nitroprusside (nitric oxide donor) and isoproterenol (β 2 -adrenergic receptor agonist). The effects of weight loss on these responses were studied in the obese groups. The response to both vasodilators was blunted, but only in obese hypertensive subjects. Weight loss normalized the response to nitroprusside but not to isoproterenol. This result suggests that obesity-related hypertension is associated with vascular smooth muscle dysfunction, which can be improved by weight loss. Blunted vasodilatation to isoproterenol suggests an abnormality on β 2 -adrenergic receptor-dependent mechanisms that may or may not depend on the endothelium. Also, mental stress-induced forearm vasodilatation was blunted in obese normotensive subjects, which was not normalized by weight loss. 2In conclusion, increased sympathetic nerve activity does not augment forearm sympathetic vascular tone. This dissociation could be due to opposing local factors (e.g. insulin, leptin) or to a different target of limb sympathoactivation (e.g. adipocytes vs. vascular). Sympathetic drive to tissues other than the peripheral circulation may play a more important role in arterial pressure elevation in obesity, either directly or indirectly.Abstract Approved: ____________________________________ Thesis Supervisor ____________________________________

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“…16 PPARa is also well known as a determinant of the development of hypertension and renal damage, especially in AT-II-induced hypertensive rats. 21,23,24,30 Induction of the renal expression of CYP4A enzymes in the kidney using fibrate compounds has been reported to lower BP in SHR, stroke-prone SHR and Dahl salt-sensitive rats. 31,32 We found the inverse pattern of PPARa expression in kidneys of WKY-HF rats compared with that in SHR-HF animals.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

et al. 2009

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We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-a activation on the intrarenal lipotoxicity associated with the renin-angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar-Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for 12 weeks. Severe intrarenal lipid accumulation was noted in the SHR rats fed an HF diet than in WYK rats fed an HF diet (Po0.05). This lipid accumulation was associated with a 70% decrease in renal PPARa expression in SHR rats, whereas an HF diet increased the expression of PPARa in WKY rats by threefold. An HF diet also activated intrarenal, not systemic, RAS and induced oxidative stress associated with reduced nitric oxide (NO) bioavailability. By contrast, fenofibrate attenuated weight gain, fat mass and insulin resistance. Fenofibrate recovered HF diet-induced decreases in intrarenal PPARa expression and fat accumulation, and abolished intrarenal RAS activation and oxidative stress in SHR-HF animals (Po0.01). These activities conferred protection against increased blood pressure (BP), glomerulosclerosis and renal inflammation. Keywords: obesity; oxidative stress; PPARa; renal inflammation; renin-angiotensin system INTRODUCTION Currently, the prevalence of hypertension and chronic renal disease continues to increase among obese individuals. 1,2 It has been suggested that the development and progression of hypertension in an obese patient induces the activation of the systemic renin-angiotensin system (RAS) and the sympathetic nervous system. 3,4 In addition, it increases asymmetric dimethylarginine concentrations and vascular tone created by the reduced bioavailability of nitric oxide (NO) owing to increased oxidative stress. 5,6 Recent reports have demonstrated that it is not the systemic but the local (tissue specific) RAS activation that causes hypertension and renal damage 7-9 associated with local oxidative stress. [10][11][12] It has been shown that oxidative stress in kidneys of diabetic animals, measured by the electron spin resonance imaging technique, 10 high-performance liquid chromatography 13 and immunohistochemistry, 14 can be ameliorated by RAS inhibition.

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Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo

Cited by 116 publications

References 54 publications

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

Sympathetic Vascular Tone in Human Obesity

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

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