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      Pentoxifylline Ameliorates Renal Tumor Necrosis Factor Expression, Sodium Retention, and Renal Hypertrophy in Diabetic Rats

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          Background/Aim: Diabetic nephropathy contributes substantially to cardiovascular morbidity and mortality associated with diabetes. Urinary tumor necrosis factor (TNF) excretion is increased during diabetes and serves as an important mediator of pathological changes during the initial stages of diabetic nephropathy, including sodium retention and renal hypertrophy. We tested the hypothesis that pentoxifylline (PTF), an agent that inhibits TNF synthesis, could prevent sodium retention and renal hypertrophy during diabetes. Methods: Proximal and distal tubule TNF expression, urinary TNF excretion, sodium retention, and renal hypertrophy were examined in control, diabetic, and PTF-treated diabetic rats. Results: TNF mRNA and protein levels were increased in proximal tubule cells isolated from diabetic rats compared to control rats. In contrast, TNF expression in distal tubule cells was not increased during diabetes. PTF prevented the increase in TNF mRNA and protein in proximal tubule cells during diabetes and reduced urinary TNF excretion. PTF therapy decreased whole animal sodium retention by enhancing urinary sodium excretion in diabetic rats. In addition, PTF reduced renal hypertrophy in diabetic rats. Conclusions: The proximal tubule is an important site of TNF production during diabetes and PTF is an effective therapy for preventing the pathological changes accompanying early diabetic nephropathy.

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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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            Transforming growth factor beta contributes to progressive diabetic nephropathy

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              Salt. A perpetrator of hypertensive target organ disease?

              Experimental and clinical data suggest salt intake to be an important factor in the pathogenesis of essential hypertension. However, the relationship between dietary sodium and blood pressure has been found to be relatively weak, perhaps because causal blood pressure levels fluctuate considerably. We hypothesized that a closer correlation could be expected between salt intake and the degree of hypertensive target organ disease. We reviewed the literature for studies dealing with 24-hour urinary sodium excretion (as a measure of salt intake) and hypertensive target organ disease as assessed by left ventricular structure and function, microproteinuria, cerebrovascular disease, and arterial compliance. Salt intake as assessed by 24-hour urinary sodium excretion was found to be a close independent determinant of left ventricular mass in 9 different studies worldwide. A reduction in dietary sodium has been shown to reduce left ventricular hypertrophy. There is clinical and experimental evidence, particularly in salt-sensitive patients, that salt intake directly affects hypertensive renal disease, cerebrovascular disease, and compliance of large arteries. The close and partially independent correlation between salt intake and hypertensive target organ disease suggests dietary sodium to be a direct perpetrator of cardiovascular disease.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                June 2004
                06 July 2004
                : 24
                : 3
                : 352-359
                Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, N.H., USA
                79121 Am J Nephrol 2004;24:352–359
                © 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: 6, References: 37, Pages: 8
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/79121
                Original Report: Laboratory Investigation


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