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      Early Blood Pressure Normalization Independent of the Class of Antihypertensive Agent Prevents Augmented Renal Fibronectin and Albuminuria in Experimental Diabetic Nephropathy

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          Abstract

          Background/Aims: This study tested the hypothesis that prevention of the development of hypertension, and not the class of antihypertensive agent, inhibits the increase in renal fibronectin and albuminuria in experimental diabetes. Methods: Four-week-old spontaneously hypertensive rats (SHR), with diabetes induced by streptozotocin, were randomized for no treatment, or treatment with captopril, amlodipine, an association of captopril and amlodipine (Cap+A) or an association of captopril and verapamil (Cap+V) for 12 weeks. Results: Systolic blood pressure increased similarly in control (187 ± 5 mm Hg, mean ± SE) and diabetic (186 ± 4) SHR and was kept within the normal range by amlodipine (131 ± 3), captopril (127 ± 3), Cap+A (134 ± 4) and Cap+V (134 ± 9, p < 0.0001). In diabetic rats, albuminuria was higher than in control SHR [geometric mean (variance), 1,213 (953–1,708) vs. 512 (213–850), p < 0.0001] and was reduced to a similar extent by amlodipine [573 (353–744), p < 0.0001], captopril [562 (238–771), p < 0.0001], Cap+A [679 (442–971), p < 0.0001] and Cap+V [748 (581–848) µg/24 h, p = 0.0002]. Renal fibronectin increased in diabetic rats (24.0 ± 3.3 densitometric units, mean ± SE) compared to control rats (9.6 ± 1.8, p = 0.0005) and was normalized by amlodipine (9.9 ± 1.0, p = 0.0001), captopril (11.2 ± 0.4, p = 0.0016), Cap+A (9.9 ± 2.0, p = 0.0004) and Cap+V (14.7 ± 4.9, p = 0.0159). Conclusion: In this model, tight blood pressure control rather than the class of antihypertensive agent was the main determinant factor in attenuating of nephropathy.

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          Most cited references 7

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          Immunochemical quantitation of antigens by single radial immunodiffusion.

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            Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice.

            Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alphaT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-beta system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of alphaT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with alphaT or control IgG, 300 microgram three times per week for 8 wk. Treatment with alphaT, but not with IgG, significantly decreased the plasma TGF-beta1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alpha1(IV) collagen and fibronectin. On the other hand, treatment with alphaT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by alphaT treatment. We conclude that chronic inhibition of the biologic actions of TGF-beta with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.
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              Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.

              Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90 mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients. The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10 mm Hg below the baseline DBP) versus moderate (80 to 89 mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease. The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 +/- 0.8/75 +/- 0.3 mm Hg versus 137 +/- 0.7/81 +/- 0.3 mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent. Over a five-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke.
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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
                2004
                July 2004
                03 May 2004
                : 27
                : 2
                : 114-120
                Affiliations
                Division of Nephrology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
                Article
                77535 Kidney Blood Press Res 2004;27:114–120
                10.1159/000077535
                15051931
                © 2004 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: 2, Tables: 1, References: 33, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/77535
                Categories
                Original Paper

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