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      The Combination of ACE Inhibition plus Sympathetic Denervation Is Superior to ACE Inhibitor Monotherapy in the Rat Renal Ablation Model

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          Abstract

          Background: The blood pressure-independent renoprotective actions of the blockade of the renin-angiotensin and the sympathetic nervous system are well documented, but monotherapies fail to completely abrogate progression. We investigated whether combined inhibition of the two systems provides additive renoprotection. Methods: After subtotal nephrectomy (SNX) or sham operation, rats underwent resection of dorsal roots, i.e. rhizotomy or sham rhizotomy. Subsequently, they received tap water or quinapril in drinking water for 16 weeks (n = 18/group). Albuminuria, blood pressure and kidneys were assessed (morphometry, immunohistochemistry). Results: At the end of the study telemetric blood pressure in SNX was 118 ± 16 mm Hg, in SNX + rhizotomy 110 ± 10 mm Hg, in SNX + quinapril 103 ± 9 mm Hg and in SNX + quinapril + rhizotomy 95 ± 7 mm Hg. Albuminuria in the respective groups was 169 ± 75, 86 ± 45, 15 ± 23 and 5 ± 4 mg/24 h. The glomerulosclerosis index was 1.40 ± 0.6, 0.80 ± 0.23, 0.37 ± 0.16 and 0.31 ± 0.15 (p < 0.001). Only combined intervention caused significant reduction of the glomerular volume and podocyte hypertrophy. The lowest indices for nitrotyrosine, NOS-1 (nNOS), TGF-β and interstitial collagen were seen with combined interventions (p < 0.05). Conclusion: In angiotensin-converting enzyme inhibitor-treated SNX animals, abrogation of sympathetic overactivity provides additional renoprotection and less nitro-oxidative stress of podocytes than single interventions. The added benefits were partially blood pressure independent.

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          Most cited references 19

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          Pathophysiology of progressive nephropathies.

           T Bertani,  G. Remuzzi (1998)
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            Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

            Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of Ang II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.
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              Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats.

              In the past, there has been considerable concern that treatment with active vitamin D might accelerate progression independent of hypercalcemia and hypercalcuria. Nevertheless, 1,25(OH)2D3 has known antiproliferative properties and has also been shown to inhibit renal growth. Since glomerular growth is a permissive factor for the development of glomerulosclerosis, we reasoned that 1,25(OH)2D3 might even attenuate progression. To test this working hypothesis we performed two experiments of 8 and 16 weeks duration, respectively, to compare subtotally nephrectomized (SNX) rats treated with ethanol and SNX treated with 1,25(OH)2D3. Control animals were sham operated and pair-fed with SNX animals. 1,25(OH)2D3 (3 ng/100 g body wt/day) was administered by osmotic minipump. 1,25(OH)2D3 had no significant effect on systolic blood pressure and only a transient effect on weight gain. SNX reduced the number of glomeruli (left kidney) from an average of 3.3 x 10(4) to 1.2 x 10(4) per kidney. Mean glomerular volume was 3.87 +/- 0.71 x 10(6) microns 3 in sham operated animals and significantly (P < 0.05) higher (10.1 +/- 1.75 x 10(6) microns 3) in untreated animals 16 weeks after SNX. Glomerular volume was significantly (P < 0.05) less in 1,25(OH)2D3 treated SNX [10.1 +/- 1.75 in ethanol vs. 7.04 +/- 1.78 in 1,25(OH)2D3 treated SNX]. In parallel, there was significantly (P < 0.01) less glomerulosclerosis [glomerulosclerosis index 1.16 +/- 0.14 in the ethanol treated SNX vs. 0.80 +/- 0.16 in SNX treated with 1,25(OH)2D3] in the eight week experiment. Albuminuria was significantly (P < 0.01) lower in 1,25(OH)2D3 treated than in ethanol treated SNX (mean 0.785 mg/24 hr, range 0.43 to 1.80, vs. 3.75 mg/24 hr, 1.29 to 14.2). The morphological data were directionally analogous in a second 16 week experiment. Only slight changes of the vascular sclerosis index and tubulointerstitial index were seen in SNX and were not affected by 1,25(OH)2D3 further. To prove that the effect of 1,25(OH)2D3 was independent of PTH, parathyreoidectomized SNX rats without or with 1,25(OH)2D3 treatment were examined seven days post-SNX. PCNA staining showed suppression of cell proliferation. Furthermore, in situ hybridization for transforming growth factor-B (TGF-beta) showed less vascular and tubular expression in 1,25(OH)2D3 treated rats. We conclude that 1,25(OH)2D3 has antiproliferative actions during the compensatory growth of nephrons in response to subtotal nephrectomy. These effects are independent of PTH. The data document that 1,25(OH)2D3 reduces renal cell proliferation and glomerular growth as well as glomerulosclerosis and albuminuria as indicators of progressive glomerular damage.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2007
                March 2007
                07 March 2007
                : 105
                : 4
                : e124-e136
                Affiliations
                aInstitute of Pathophysiology, Semmelweis University, Budapest, and bDepartment of Pathology, University of Szeged, Szeged, Hungary; cDepartment of Internal Medicine and dDepartment of Pathology, University of Heidelberg, Heidelberg, and eDepartment of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
                Article
                100494 Nephron Exp Nephrol 2007;105:e124–e136
                10.1159/000100494
                17347582
                © 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: 5, Tables: 7, References: 35, Pages: 1
                Categories
                Original Paper

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