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      Statin Monotherapy Attenuates Renal Injury in a Salt-Sensitive Hypertension Model of Renal Disease

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          Abstract

          Background: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. Methods: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-β<sub>1</sub>, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). Results: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 ± 7.3 vs. 84.4 ± 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-β did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 ± 6.6 vs. 50.2 ± 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 ± 0.40 vs. 4.07 ± 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. Conclusion: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.

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          Most cited references 26

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.

            Angiographic studies of the regression of coronary artery disease are invasive and costly, and they permit only limited assessment of changes in the extent of atherosclerotic disease. Electron-beam computed tomography (CT) is noninvasive and inexpensive. The entire coronary-artery tree can be studied during a single imaging session, and the volume of coronary calcification as quantified with this technique correlates closely with the total burden of atherosclerotic plaque. We conducted a retrospective study of 149 patients (61 percent men and 39 percent women; age range, 32 to 75 years) with no history of coronary artery disease who were referred by their primary care physicians for screening electron-beam CT. All patients underwent base-line scanning and follow-up assessment after a minimum of 12 months (range, 12 to 15), and a volumetric calcium score was calculated as an estimate of the total burden of plaque. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors was begun at the discretion of the referring physician. Serial measurements of low-density lipoprotein (LDL) cholesterol were obtained, and the change in the calcium-volume score was correlated with average LDL cholesterol levels. One hundred five patients (70 percent) received treatment with HMG-CoA reductase inhibitors, and 44 patients (30 percent) did not. At follow-up, a net reduction in the calcium-volume score was observed only in the 65 treated patients whose final LDL cholesterol levels were less than 120 mg per deciliter (3.10 mmol per liter) (mean [+/-SD] change in the score, -7+/-23 percent; P=0.01). Untreated patients had an average LDL cholesterol level of at least 120 mg per deciliter and at the time of follow-up had a significant net increase in mean calcium-volume score (mean change, +52+/-36 percent; P<0.001). The 40 treated patients who had average LDL cholesterol levels of at least 120 mg per deciliter had a measurable increase in mean calcium-volume score (25+/-22 percent, P<0.001), although it was smaller than the increase in the untreated patients. The extent to which the volume of atherosclerotic plaque decreased, stabilized, or increased was directly related to treatment with HMG-CoA reductase inhibitors and the resulting serum LDL cholesterol levels. These changes can be determined noninvasively by electron-beam CT and quantified with use of a calcium-volume score.
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              Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.

              Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In these studies we investigated the effects of chronic inhibition of basal NO synthesis in the rat for a 2-mo period. Significant systemic hypertension developed in chronically NO-blocked rats compared to controls. Marked renal vasoconstriction was also observed with elevations in glomerular blood pressure (PGC) and reductions in the glomerular capillary ultrafiltration coefficient (Kf). Chronically NO-blocked rats also develop proteinuria and glomerular sclerotic injury compared to controls. These studies therefore describe a new model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous NO synthesis. These observations highlight the importance of the endogenous NO system in control of normal vascular tone and suggest that hypertensive states may result from relative NO deficiency.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2005
                December 2005
                14 November 2005
                : 101
                : 4
                : p82-p91
                Affiliations
                Internal Medicine, Renal Division, University of São Paulo, São Paulo, Brazil
                Article
                87576 Nephron Physiol 2005;101:p82–p91
                10.1159/000087576
                16113589
                © 2005 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: 5, Tables: 1, References: 40, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/87576
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                Original Paper

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