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      Thioredoxin-Interacting Protein: A Potential Therapeutic Target for Treatment of Progressive Fibrosis in Diabetic Nephropathy

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          Abstract

          Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the antioxidant thioredoxin, and a critical agent in the in vivo regulation of glucose. The well-described induction of TXNIP by high glucose may represent an important pathogenic trigger of complications arising in the diabetic environment, with sustained overexpression of TXNIP triggering the increased production of reactive oxygen species and collagen, both major contributors to the development of diabetic nephropathy (DN). To examine a possible therapeutic role for targeted TXNIP inhibition in DN, transgenic (mRen-2)27 rats were rendered diabetic with streptozotocin and then treated with 20 μ<smlcap>M</smlcap> TXNIP deoxyribozyme (DNAzyme) delivered continuously over 12 weeks by an implanted osmotic mini-pump. Renal injury was measured using biochemical parameters of kidney function along with histological markers of damage. Catalytic activity of TXNIP DNAzyme was determined by TXNIP gene and peptide expression in the rat kidneys. TXNIP DNAzyme localization was demonstrated with a fluorescent-labelled TXNIP DNAzyme. A panel of markers was used to assess the extent of oxidative stress and renal fibrosis including superoxide level, nitrotyrosine staining, TGF-β1, NLRP3 and collagen IV expression. Fluorescent-labelled TXNIP DNAzyme was localized to tubulo-epithelial cells, but was not identified in glomeruli or endothelial cells. Elevated renal cortical TXNIP gene and protein expression seen in kidneys of DN animals were significantly attenuated by TXNIP DNAzyme (p < 0.05). Downstream markers of TXNIP activity, particularly oxidative stress, inflammasome signalling, tubulo-interstitial fibrosis and collagen deposition, were also attenuated in the tubulo-interstitium of DN rats treated with TXNIP DNAzyme. Consistent with the identified site of action of the DNAzyme, the effects of the TXNIP inhibition were limited to the tubulo-interstitial compartment. This study supports the role of TXNIP as an important mediator of progressive tubulo-interstitial fibrosis in DN, and also supports the notion of TXNIP inhibition as a potential new therapeutic target for DN.

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          Most cited references 42

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          Thioredoxin-interacting protein links oxidative stress to inflammasome activation.

          The NLRP3 inflammasome has a major role in regulating innate immunity. Deregulated inflammasome activity is associated with several inflammatory diseases, yet little is known about the signaling pathways that lead to its activation. Here we show that NLRP3 interacted with thioredoxin (TRX)-interacting protein (TXNIP), a protein linked to insulin resistance. Inflammasome activators such as uric acid crystals induced the dissociation of TXNIP from thioredoxin in a reactive oxygen species (ROS)-sensitive manner and allowed it to bind NLRP3. TXNIP deficiency impaired activation of the NLRP3 inflammasome and subsequent secretion of interleukin 1beta (IL-1beta). Akin to Txnip(-/-) mice, Nlrp3(-/-) mice showed improved glucose tolerance and insulin sensitivity. The participation of TXNIP in the NLRP3 inflammasome activation may provide a mechanistic link to the observed involvement of IL-1beta in the pathogenesis of type 2 diabetes.
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            The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?

            Although the glomerulus, particularly the mesangium, has been the focus of intense investigation in diabetes, tubulointerstitial injury is also a major feature of diabetic nephropathy and an important predictor of renal dysfunction. The renal tubule in diabetes is subject to both direct and indirect pathogenetic influences as a consequence of its position in the nephron and its resorptive function. On exposure to glucose, proximal tubular cells elaborate vasoactive hormones, including angiotensin II and injurious cytokines such as transforming growth factor-beta (TGF-beta), as well as extracellular matrix proteins. In turn, angiotensin II may further increase TGF-beta expression in both proximal tubular and interstitial cells, thus amplifying the stimulus to fibrogenesis in the renal tubulointerstitium. In addition to these mostly direct influences, the renal tubule, particularly its proximal segment, is exposed to glomerular effluent. In the diabetic state, this includes large quantities of advanced glycation end products and glucose and, at later stages in the evolution of diabetic nephropathy, protein, all of which are factors that may induce TGF-beta expression and fibrosis. Diabetic nephropathy should therefore be viewed as a disease affecting the entire nephron. Continued exploration into tubulointerstitial disease in addition to glomerular injury in diabetes may help provide further insights into the pathogenesis of diabetic nephropathy and additional targets for therapeutic intervention.
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              A general purpose RNA-cleaving DNA enzyme

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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2015
                February 2015
                31 January 2015
                : 129
                : 2
                : 109-127
                Affiliations
                aDepartment of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Vic., and bDepartment of Nephrology, St. Vincent's Hospital, Fitzroy, Vic., Australia
                Author notes
                *Robyn G. Langham, Department of Nephrology, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065 (Australia), E-Mail rlangham@unimelb.edu.au
                368238 Nephron 2015;129:109-127
                10.1159/000368238
                25662516
                © 2015 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.

                Counts
                Figures: 12, Tables: 1, References: 47, Pages: 19
                Categories
                Experimental Nephrology: Original Paper

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