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      IL6 Suppression Provides Renal Protection Independent of Blood Pressure in a Murine Model of Salt-Sensitive Hypertension

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          Abstract

          Impaired cytochrome P450 epoxygenase enzyme (Cyp2c) regulation contributes to renal damage in angiotensin salt-sensitive hypertension (ANG/HS). We hypothesized that interleukin-6 null mice (IL6–/–) would improve Cyp2c regulation and reduce renal damage in hypertensive mice fed a high salt diet. Systolic blood pressure increased to a greater extent in ANG/HS hypertension as compared to angiotensin (ANG) hypertension but blood pressure did not differ between WT and IL6–/– hypertensive groups. Albuminuria, a marker for renal injury, increased significantly in ANG/HS hypertension in WT mice (5,113 ± 1,050 µg/day) and was attenuated in the ANG/HS IL6–/– group (1,306 ± 385 µg/day). Renal Cyp2c protein expression significantly decreased with ANG/HS hypertension in WT mice as compared to high salt alone. However, the ability to upregulate Cyp2c expression in response to a high salt diet was restored in the ANG/HS IL6 deficient hypertensive mice. Renal expression of soluble epoxide hydrolase, which inactivates protective epoxygenase metabolites, was significantly reduced in ANG/HS IL6–/– hypertensive mice compared to the ANG/HS WT group. These data suggest that IL6, while having no effect on blood pressure, impairs regulation of epoxygenase producing Cyp2c, which could contribute to the development of renal injury in angiotensin salt-sensitive hypertension.

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          Most cited references 21

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          Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction.

          The aim of this study was to evaluate the prognostic value of interleukin-6 (IL-6) for myocardial infarction (MI) and mortality in a population with stable coronary artery disease (CAD) during a mean period of 6.3 years. IL-6 is a major proinflammatory cytokine of acute phase response; elevated levels are associated with worse prognosis in unstable angina and after acute MI. However, data regarding its long-term prognostic value in stable CAD are limited and controversial. A nested case-control study design was used. Of 3,090 patients with stable CAD, 129 with an adequate blood sample for IL-6 and who reached the end points (MI or sudden death) were randomly selected. Each case was 1:1 matched with 129 controls (alive at the end of the study and free of cardiovascular events) according to age, gender, and treatment. Of the 129 cases, 113 had a MI as the initial event, and for the other 16 the initial event was sudden death. There were 8 patients who first had a MI and later died suddenly. IL-6 was significantly higher in cases (2.34 pg/ml) than in controls (1.65 pg/ml) (p = 0.0004). IL-6 was significantly correlated with C-reactive protein (r = 0.2, p = 0.002); a borderline significance was also found for fibrinogen (r = 0.11, p = 0.07). Each increase of 1 pg/ml in IL-6 was associated with a 1.70 (range 1.23 to 2.45) increased relative odds of subsequent MI or sudden death. Events rate per 1,000 patients-years for the 5 quintiles of IL-6 were 72.26, 89.61, 79.76, 142.53, and 181.08, respectively (p <0.0001). A significantly higher risk in the upper quintile was found (odds ratio, 3.44; 95% confidence interval 1.57 to 8.13). In conclusion, elevated IL-6 levels are strongly associated with future cardiac events and mortality in a population with stable CAD during a long-term follow-up.
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            Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases.

             John D. Imig (2005)
            Renal epoxygenase metabolites are involved in blood flow regulation and long-term blood pressure control. One feature of renal and cardiovascular diseases is the inability of the kidney to properly increase epoxyeicosatrienoic acid (EET) levels. Others (Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte PM, and Weston AH. Trends Phamacol Sci 23: 374-380, 2002; Campbell WB, Gebremedhin D, Pratt PF, and Harder DR. Circ Res 78: 415-423, 1996; Capdevila JH and Falck JR. Biochem Biophys Res Commun 285: 571-576, 2001; Roman RJ. Physiol Rev 82: 131-185, 2002; Zeldin DC. J Biol Chem 276: 36059-36062, 2001) and we (Imig JD, Falck JR, Wei S, and Capdevila JH. J Vasc Res 38: 247-255, 2001; Imig JD, Zhao X, Capdevila JH, Morisseau C, and Hammock BD. Hypertension 39: 690-694, 2002; Zhao X, Pollock DM, Inscho EW, Zeldin DC, and Imig JD. Hypertension 41: 709-714, 2003; Zhao X, Pollock DM, Zeldin DC, and Imig JD. Hypertension 42: 775-780, 2003) have provided compelling evidence that cytochrome P-450-derived EETs have antihypertensive properties and are endothelially derived hyperpolarizing factors (EDHFs) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during renal and cardiovascular diseases. A tactic that has been used to increase EET levels has been inhibition of the soluble epoxide hydrolase enzyme. Epoxide hydrolase inhibitors have been demonstrated to be antihypertensive and renal protective. Thus the renal and cardiovascular protective actions of increasing epoxygenase levels could be translated to therapies for preventing end-organ damage.
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              Proinflammatory actions of angiotensins.

              Many experimental data have suggested that the renin-angiotensin system participates in immune and inflammatory responses. Angiotensin II is involved in several steps of the inflammatory process: mononuclear cells respond to angiotensin II stimulation (cell proliferation and chemotaxis); angiotensin II regulates the recruitment of proinflammatory cells into the site of injury (mediated by the expression of vascular permeability factors, adhesion molecules and chemokines by resident cells); inflammatory cells can produce angiotensin II, and might therefore contribute to the perpetuation of tissue damage. In this review, we summarize the proinflammatory properties of angiotensin II, to demonstrate the novel role of this vasoactive peptide as a true cytokine. We will show the information obtained as a result of the pharmacological blockade of the renin angiotensin system, which has demonstrated that this system is involved in immune and inflammatory diseases. In this aspect, we discuss the molecular mechanism of angiotensin II-induced tissue damage, as well as its contribution to the pathogenesis of several diseases, including atherosclerosis, hypertension and renal damage, showing that angiotensin II plays an active role in the inflammatory response of these diseases.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2007
                July 2007
                15 June 2007
                : 30
                : 4
                : 195-202
                Affiliations
                Departments of aVascular Biology, bPathology, and cPhysiology, Medical College of Georgia, Augusta, Ga., USA
                Article
                104094 Kidney Blood Press Res 2007;30:195–202
                10.1159/000104094
                17575466
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 30, Pages: 8
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Interleukin-6, Hypertension, Renal damage, Inflammation, Angiotensin II

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