Angiotensin II hypertension is attenuated in interleukin-6 knockout mice

Lee, Dexter L.; Sturgis, LaShon; Labazi, Hicham; Osborne, James B.; Fleming, Cassandra; Pollock, Jennifer S.; Manhiani, Marlina; Imig, John D.; Brands, Michael

doi:10.1152/ajpheart.00708.2005

Cited by 225 publications

(216 citation statements)

References 36 publications

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“…26 In contrast to our findings, deletion of IL-6 did not influence the pressor response to high-dose Ang II on a normal salt diet. 27 Here, considerably lower Ang II doses that are still sufficient to generate pressor responses were used, and it was found that deletion of IL-6 was fully sufficient to prevent BP eleva- Ϫ/Ϫ aortic rings after preincubation with 1 mol/L Ang II (n ϭ 8).…”

Section: Discussioncontrasting

confidence: 99%

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Coles

Fielding

Rose-John

et al. 2007

The American Journal of Pathology

120

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Interleukin (IL)-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130).Here, we investigated the role of these IL-6R components in hypertension and vascular hypertrophy in mice. Angiotensin (Ang) II (1.1 mg/kg/day) caused hypertension and cardiac/aortic hypertrophy in wildtype, but not IL-6 ؊/؊ , mice throughout 7 days. A recombinant dimeric soluble gp130 (sgp130Fc; 50 to 100 g, i.p.) blocked Ang II hypertension but not hypertrophy in wild-type mice. Cognate IL-6R was detected in aortic smooth muscle, but its levels and those of plasma sIL-6R were ϳ50% decreased in IL-6 ؊/؊ mice. Ang II infusion activated signal transducer and activator of transcription-3 in heart of WT and decreased Ang II receptor 1 (ATR1) expression in aorta. Both responses were unaffected by sgp130Fc and absent in IL-6 ؊/؊ mice. In summary, we show that IL-6 trans-signaling is required for Ang II-dependent hypertension, but that hypertrophy, down-regulation of AT1R, and cardiac signal transducer and activator of transcription-3 activation are mediated via cognate IL-6R. These data show that IL-6 responses in a single disease context are governed by both modes of IL-6 signaling, with each pathway eliciting different outcomes. Inhibition of IL-6 signaling is suggested as a potential therapy for hypertension and cardiac hypertrophy. There is emerging evidence for a role of interleukin (IL)-6 and its related cytokines in angiotensin (Ang) II-dependent vascular dysfunction. Plasma levels of IL-6 are strongly associated with hypertension in humans and can be decreased by administration of Ang II receptor antagonists.

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Section: Discussioncontrasting

confidence: 99%

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Coles

Fielding

Rose-John

et al. 2007

The American Journal of Pathology

120

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“…[7][8][9][10][11] Although there is experimental evidence that proinflammatory cytokines may activate the sympathetic nervous system, 11 it is not clear whether cytokines such as IL-6 activate the renin-angiotensin system. We reported previously that plasma renin activity is not elevated in RUPP rats.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6] Important blood pressure regulatory systems, such as the renin-angiotensin system, sympathetic nervous system, and endothelial factors, interact with proinflammatory cytokines, such as IL-6 and TNF-␣. [7][8][9][10][11][12] Angiotensin II not only enhances the synthesis of TNF-␣ and IL-6, it also seems that IL-6 may play an important role in mediating the hypertension produced by angiotensin II in mice. 9 Proinflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation.…”

mentioning

confidence: 99%

“…[7][8][9][10][11][12] Angiotensin II not only enhances the synthesis of TNF-␣ and IL-6, it also seems that IL-6 may play an important role in mediating the hypertension produced by angiotensin II in mice. 9 Proinflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation. [12][13][14][15][16] TNF-␣ and IL-6 have both been shown to induce structural, as well as functional, alterations in endothelial cells.…”

mentioning

confidence: 99%

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Hypertension Produced by Reductions in Uterine Perfusion in the Pregnant Rat

et al. 2006

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Abstract-The purpose of this study was to determine the role of interleukin (IL) 6 in mediating the increase in arterial pressure (AP) in response to chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats. AP was higher in RUPP rats (138Ϯ1 mm Hg) than in normal pregnant (NP) rats (104Ϯ1 mm Hg). Serum IL-6 levels in the RUPP rats were 104.5Ϯ28.6 pg/mL as compared with 36.6Ϯ7.4 pg/mL in NP rats. To determine the long-term effects of a 2-to 3-fold elevation in plasma IL-6 on renal function and AP in pregnant rats, we infused IL-6 for 5 days (2.5 ng/day) in NP rats starting at day 14 of gestation. Five days later, serum IL-6 levels were 55.5Ϯ6.5 pg/mL in the control NP rats and 157.0Ϯ36.1 pg/mL in the IL-6 -treated NP rats. AP was higher in the IL-6 -treated NP rats (115Ϯ3 mm Hg) as compared with NP controls (101Ϯ1 mm Hg) at day 19 of gestation. Renal plasma flow and GFR were lower in the IL-6 -treated NP rats than in the NP group. IL-6 increased plasma renin activity but did not affect endothelin in IL-6 -treated NP rats. In contrast to the NP rats, IL-6 had no effect on AP or renal hemodynamics in virgin rats. In summary, these data indicate that plasma IL-6 is elevated in response to chronic reductions in uterine perfusion in pregnant rats and that a comparable elevation in plasma IL-6 increases AP and reduces renal function in pregnant rats.

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“…IL-6 is a cytokine that has been demonstrated to be associated with renal injury [32,33]. Renal IL-6 results in macrophage accumulation in the kidney, stimulates the expression of C-reactive protein, can increase TNF-α and inhibits nitric oxide [34,35].…”

Section: Renal Damage and Cardiometabolic Syndromementioning

confidence: 99%

Eicosanoids and renal damage in cardiometabolic syndrome

Imig

2008

Expert Opinion on Drug Metabolism & Toxicology

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Obesity, hypertension and type 2 diabetes are major contributing factors to the increase in the number of patients that have chronic kidney disease. The clustering of visceral obesity and cardiovascular risk factors has been designated metabolic syndrome or cardiometabolic syndrome. Cardiometabolic syndrome is associated with a complex systemic inflammatory state that has been implicated in medically important complications including endothelial dysfunction. Inflammation, endothelial dysfunction, and insulin resistance are interrelated and have reciprocal relationships that link cardiovascular and metabolic diseases. Ultimately, cardiometabolic syndrome increases the risk for cardiovascular events and end organ damage. Although the number of patients with cardiometabolic syndrome is escalating, therapeutic approaches have not been developed that provide protection to the kidney. Eicosanoids are altered in cardiometabolic syndrome and contribute the progression of renal injury. The anti-hypertensive and anti-inflammatory actions of epoxides and soluble epoxide hydrolase inhibitors make these attractive eicosanoid therapeutic targets for chronic kidney disease in patients with cardiometabolic syndrome. Keywordskidney; epoxyeicosatrienoic acids; epoxide hydrolase; obesity; cytokines; inflammation Cardiometabolic SyndromeIn recent years, the number of obese people in the world is growing rapidly and has reached epidemic status. Obesity is the central phenotype in metabolic syndrome, also known as cardiometabolic syndrome that clusters with other cardiovascular risk factors. These other cardiovascular risk factors include hypertension, type 2 diabetes, insulin resistance, low high-density lipoproteins (HDL) cholesterol, elevated triglycerides, microalbuminuria, and atherosclerosis [1,2,3] (Figure 1). The Adult treatment Panel II of the National Cholesterol Education Program has defined metabolic syndrome as any three of the following five traits: visceral obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and impaired fasting glucose [4]. Although obesity is the phenotypic hallmark of cardiometabolic syndrome, the other risk factors that manifest in individuals varies greatly. Blood pressure elevation in obese individuals is closely related to weight gain; however, not all obese individuals become hypertensive [5][6][7][8]. The relationship between obesity and hypertension is well established but the exact consequences to end organ damage remains unknown. Interestingly, hypertension and diabetes account for seventy percent of patients with end stage renal disease (ESRD) and the number of patients with ESRD will double in this decade [9,10]. One of the main reasons for the doubling in ESRD patients is the increase in obesity related type 2 diabetes and its co-existence with hypertension.

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Angiotensin II hypertension is attenuated in interleukin-6 knockout mice

Cited by 225 publications

References 36 publications

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Hypertension Produced by Reductions in Uterine Perfusion in the Pregnant Rat

Eicosanoids and renal damage in cardiometabolic syndrome

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