Original Report: Laboratory Investigation
Neutralization of Tumor Necrosis Factor-Alpha Reduces Renal Fibrosis and Hypertension in Rats with Renal FailureTherrien F.J. · Agharazii M. · Lebel M. · Larivière R.
Nephrology and Hypertension, CHUQ Research Centre, L’Hôtel-Dieu de Québec Hospital and Department of Medicine, Université Laval, Quebec, Que., Canada
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: Increased production of tumor necrosis factor-α (TNF-α) in chronic kidney disease may be involved in the progression of renal failure and injury, and cardiovascular disease. We investigated the effect of TNF-α neutralization on renal failure, inflammation and fibrosis, and blood pressure in rats with renal failure. Methods and Results: Renal failure was induced by renal mass reduction and the animals were treated with PEG-sTNFR1, a pegylated form of soluble TNF type 1 receptor that neutralizes TNF-α, for 6 weeks. Systolic, diastolic and mean arterial pressures were higher in renal failure rats that were associated with increased serum creatinine, albuminuria and renal injury comprised of blood vessel media hypertrophy, focal and segmental glomerulosclerosis, tubular atrophy and interstitial inflammation and fibrosis. These changes were associated with greater levels of TNF-α, transforming growth factor (TGF)-β1, nuclear transcription factor NF-ĸB and cytosolic phospho-IĸB-α, and inflammatory markers expression (ICAM-1, VCAM-1 and MCP-1). Moreover, endothelin (ET)-1 production was also increased, whereas nitric oxide (NO) release was decreased. TNF-α neutralization reduced hypertension, albuminuria and renal inflammation and fibrosis, which were coupled to a reduction in renal NF-ĸB activation, inflammatory markers expression, TGF-β1 and ET-1 production, and an increase in NO release. Conclusion: Neutralization of TNF-α in rats with renal failure decreases NF-ĸB activity that is associated with a reduction in renal TGF-β1 and ET-1 production, and an improvement of NO release. These effects likely reduce renal inflammation and fibrosis, and blood pressure indicating a pivotal role for TNF-α, at least, in the progression of renal injury.
© 2012 S. Karger AG, Basel
- Foley RN, Parfrey PS, Sarnak MJ: Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998;9:S16–S23.
- Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimburger O, Cederholm T, Girndt M: IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia–the good, the bad, and the ugly. Kidney Int 2005;67:1216–1233.
- Navarro JF, Mora-Fernandez C: The role of TNF-alpha in diabetic nephropathy: Pathogenic and therapeutic implications. Cytokine Growth Factor Rev 2006;17:441–450.
- Naya M, Tsukamoto T, Morita K, Katoh C, Furumoto T, Fujii S, Tamaki N, Tsutsui H: Plasma interleukin-6 and tumor necrosis factor-alpha can predict coronary endothelial dysfunction in hypertensive patients. Hypertens Res 2007;30:541–548.
- Guijarro C, Egido J: Transcription factor-kappa b (NF-kappa b) and renal disease. Kidney Int 2001;59:415–424.
- Elmarakby AA, Quigley JE, Imig JD, Pollock JS, Pollock DM: TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2008;294:R76–R83.
- Meldrum KK, Metcalfe P, Leslie JA, Misseri R, Hile KL, Meldrum DR: TNF-alpha neutralization decreases nuclear factor-kappaB activation and apoptosis during renal obstruction. J Surg Res 2006;131:182–188.
- Khan SB, Cook HT, Bhangal G, Smith J, Tam FW, Pusey CD: Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis. Kidney Int 2005;67:1812–1820.
- Sean Eardley K, Cockwell P: Macrophages and progressive tubulointerstitial disease. Kidney Int 2005;68:437–455.
- Sumagin R, Lomakina E, Sarelius IH: Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling. Am J Physiol Heart Circ Physiol 2008;295:H969–H977.
- Henke N, Schmidt-Ullrich R, Dechend R, Park JK, Qadri F, Wellner M, Obst M, Gross V, Dietz R, Luft FC, Scheidereit C, Muller DN: Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage. Circ Res 2007;101:268–276.
- Bani-Hani AH, Campbell MT, Meldrum DR, Meldrum KK: Cytokines in epithelial-mesenchymal transition: a new insight into obstructive nephropathy. J Urol 2008;180:461–468.
- Bates RC, Mercurio AM: Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 2003;14:1790–1800.
- Meldrum KK, Misseri R, Metcalfe P, Dinarello CA, Hile KL, Meldrum DR: TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction. Am J Physiol Regul Integr Comp Physiol 2007;292:R1456–R1464.
- Guo G, Morrissey J, McCracken R, Tolley T, Klahr S: Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy. Am J Physiol 1999;277:F766–F772.
- Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Larivière R: Neutralization of transforming growth factor-β attenuates hypertension and prevents renal injury in uremic rats. J Hypertens 2005;23:1895–1903.
- Corder R, Carrier M, Khan N, Klemm P, Vane JR: Cytokine regulation of endothelin-1 release from bovine aortic endothelial cells. J Cardiovasc Pharmacol 1995;26 Suppl 3:S56–S58.
- Marsden PA, Brenner BM: Transcriptional regulation of the endothelin-1 gene by TNFa. Am J Physiol 1992;262:C854–C861.
- Stenvinkel P: Endothelial dysfunction and inflammation – is there a link? Nephrol Dial Transplant 2001;16:1968–1971.
- Yoshizumi M, Perreila MA, Burnett JCJ, Lee ME: Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res 1993;73:205–209.
- Zhang H, Park Y, Wu J, Chen X, Lee S, Yang J, Dellsperger KC, Zhang C: Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond) 2009;116:219–230.
- Larivière R, Lebel M: Endothelin-1 in chronic renal failure and hypertension. Can J Physiol Pharmacol 2003;81:607–621.
- Dumont Y, D’Amours M, Lebel M, Larivière R: Blood pressure-independent effects of angiotensin AT1 receptor blockade on renal endothelin-1 production in hypertensive uremic rats. J Hypertens 2001;19:1479–1487.
- Morris ST, McMurray JJ, Spiers A, Jardine AG: Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 2001;60:1077–1082.
- Vallance P, Leone A, Calver A, Collier J, Moncada S: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339:572–575.
- Aiello S, Noris M, Todeschini M, Zappella S, Foglieni C, Benigni A, Corna D, Zoja C, Cavallotti D, Remuzzi G: Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int 1997;52:171–181.
- Vaziri ND, Ni Z, Wang X, Oveisi F, Zhou X: Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol 1998;274:F642–F649.
- Larivière R, D’Amours M, Lebel M, Kingma I, Grose JH, Caron L: Increased immunoreactive endothelin-1 levels in blood vessels and glomeruli of rats with reduced renal mass. Kidney Blood Pressure Res 1997;20:372–380.
- Edwards CK 3rd: Pegylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases. Ann Rheum Dis 1999;58(suppl 1):I73–I81.
- Larivière R, Lebel M, Kingma I, Grose JH, Boucher D: Effects of losartan and captopril on endothelin-1 production in blood vessels and glomeruli of rats with reduced renal mass. Am J Hypertens 1998;11:989–997.
- Bendele AM, McComb J, Gould T, Frazier J, Chlipala E, Seely J, Kieft G, Edwards CK 3rd: Effects of pegylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) alone and in combination with methotrexate in adjuvant arthritic rats. Clin Exp Rheumatol 1999;17:553–560.
- Misseri R, Meldrum DR, Dinarello CA, Dagher P, Hile KL, Rink RC, Meldrum KK: TNF-alpha mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling. Am J Physiol Renal Physiol 2005;288:F406-F411.
- Dumont Y, D’Amours M, Lebel M, Larivière R: Supplementation with a low dose of L-arginine reduces blood pressure and endothelin-1 production in hypertensive uraemic rats. Nephrol Dial Transplant 2001;16:746–754.
- Lebel M, Rodrigue ME, Agharazii M, Lariviere R: Antihypertensive and renal protective effects of renin-angiotensin system blockade in uremic rats treated with erythropoietin. Am J Hypertens 2006;19:1286–1292.
- Liu W, Saint DA: A new quantitative method of real time reverse transcription polymerase chain reaction assay based on simulation of polymerase chain reaction kinetics. Anal Biochem 2002;302:52–59.
- Yang J, Liu Y: Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol 2001;159:1465–1475.
- Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, Nikolic-Paterson DJ, Atkins RC, Lan HY: Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 1998;54:864–876.
- Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY: Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 1999;56:1455–1467.
- Gomez-Garre D, Ruiz Ortega M, Ortego M, Largo R, Lopez Armada MJ, Plaza JJ, Gonzalez E, Egido J: Effects and interactions of endothelin-1 and angiotensin ii on matrix protein expression and synthesis and mesangial cell growth. Hypertension 1996;27:885–892.
- Rancourt ME, Rodrigue ME, Agharazii M, Lariviere R, Lebel M: Role of oxidative stress in erythropoietin-induced hypertension in uremic rats. Am J Hypertens 2010;23:314–320.
- Vila E, Salaices M: Cytokines and vascular reactivity in resistance arteries. Am J Physiol Heart Circ Physiol 2005;288:H1016–H1021.
- Patel JN, Jager A, Schalkwijk C, Corder R, Douthwaite JA, Yudkin JS, Coppack SW, Stehouwer CD: Effects of tumour necrosis factor-alpha in the human forearm: blood flow and endothelin-1 release. Clin Sci 2002;103:409–415.
- Nakamura M, Yoshida H, Arakawa N, Saitoh S, Satoh M, Hiramori K: Effects of tumor necrosis factor-alpha on basal and stimulated endothelium-dependent vasomotion in human resistance vessel. J Cardiovasc Pharmacol 2000;36:487–492.
- Ohkita M, Takaoka M, Shiota Y, Nojiri R, Sugii M, Matsumura Y: A nuclear factor-kappab inhibitor bay 11–7082 suppresses endothelin-1 production in cultured vascular endothelial cells. Jpn J Pharmacol 2002;89:81–84.
- LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP: Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. Hypertension 2005;46:82–86.
- Waldow T, Witt W, Weber E, Matschke K: Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and nfkappab activation in endothelial cells. Nitric Oxide 2006;15:103–113.
- Shahid M, Francis J, Majid DS: Tumor necrosis factor-alpha induces renal vasoconstriction as well as natriuresis in mice. Am J Physiol Renal Physiol 2008;295:F1836–1844.
- Gong R, Rifai A, Tolbert EM, Biswas P, Centracchio JN, Dworkin LD: Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and rantes. J Am Soc Nephrol 2004;15:2868–2881.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: 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.