Background: Inflammatory events antecede established renal injury in rats with 5/6 renal ablation (Nx), as indicated by the beneficial effects of early, uninterrupted treatment with mycophenolate mofetil (MMF). Angiotensin II also exerts a major pathogenic role at this initial phase. We investigated whether losartan (L) or L+MMF treatment, started early, and L+MMF treatment, started late, would exert lasting renoprotection in Nx even after being discontinued. Methods: Adult male Munich-Wistar rats underwent Nx and were divided into three groups: Nx (untreated), NxL (given L), and NxLMMF (given L and MMF). Protocol 1: treatments began on day 1, and ceased on day 30, after Nx. Protocol 2: L+MMF treatment began on day 30 and ceased on day 60. Results: Protocol 1: on day 30, hypertension, albuminuria and renal injury were strongly attenuated in Groups NxL and NxLMMF. On day 120, these abnormalities were still attenuated in group NxLMMF. Protocol 2: on day 120, all parameters were similar between this late NxLMMF group and untreated Nx. Conclusion: In Nx, temporary suppression of early, transitory hemodynamic/inflammatory phenomena affords relatively durable renoprotection even after treatment discontinuation. This effect is not obtained with similar temporary treatment initiated later in the course of renal disease.

Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 1986;77:1993–2000.
Fujihara CK, Malheiros DMAC, Zatz R, Noronha IL: Mycophenolate mofetil attenuates renal injury in the rat remnant kidney. Kidney Int 1998;54:1510–1519.
Fujihara CK, Malheiros DM, Zatz R: Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model. Am J Physiol Renal Physiol 2007;292:F1810–F1818.
Floege J, Alpers CE, Burns MW, Pritzl P, Gordon K, Couser WG, Johnson RJ: Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 1992;66:485–497.
Kliem V, Johnson RJ, Alpers CE, Yoshimura A, Couser WG, Koch KM, Floege J: Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats. Kidney Int 1996;49:666–678.
Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera-Acosta J, Tapia E: Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999;55:945–955.
Yang N, Wu LL, Nikolic-Paterson DJ, Ng YY, Yang WC, Mu W, Gilbert RE, Cooper ME, Atkins RC, Lan HY: Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney. Nephrol Dial Transplant 1998;13:1967–1974.
Lafayette RA, Mayer G, Park SK, Meyer TW: Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992;90:766–771.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: the Collaborative Study Group. N Engl J Med 1993;329:1456–1462.
Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency: the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996;334:939–945.
Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE: Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system. Kidney Int 1997;51:1553–1567.
Fujihara CK, Noronha IL, Malheiros DMAC, Antunes GR, Oliveira IB, Zatz R: Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney. J Am Soc Nephrol 2000;11:283–290.
Goncalves AR, Fujihara CK, Mattar AL, Malheiros DMAC, Noronha IL, De Nucci G, Zatz R: Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory. Am J Physiol Renal Physiol 2004;286:F945–F954.
Yamamoto M, Fukui M, Shou I, Wang LN, Sekizuka K, Suzuki S, Shirato I, Tomino Y: Effects of treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AIIRA) on renal function and glomerular injury in subtotal nephrectomized rats. J Clin Lab Anal 1997;11:53–62.
Meyer TW, Anderson S, Rennke HG, Brenner BM: Reversing glomerular hypertension stabilizes established glomerular injury. Kidney Int 1987;31:752–759.
Jepsen FL, Mortensen PB: Interstitial fibrosis of the renal cortex in minimal change lesion and its correlation with renal function: a quantitative study. Virchows Arch A Pathol Anat Histol 1979;383:265–270.
Wallenstein S, Zucker CL, Fleiss JL: Some statistical methods useful in circulation research. Circ Res 1980;47:1–9.
Fujihara CK, Sena CR, Malheiros DM, Mattar AL, Zatz R: Short-term nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury. Am J Physiol Renal Physiol 2006;290:F632–F640.
Badid C, Vincent M, McGregor B, Melin M, Hadj-Aissa A, Veysseyre C, Hartmann DJ, Desmouliere A, Laville M: Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney. Kidney Int 2000;58:51–61.
Hauser IA, Renders L, Radeke HH, Sterzel RB, Goppelt-Struebe M: Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion. Nephrol Dial Transplant 1999;14:58–63.
Remuzzi G, Zoja C, Gagliardini E, Corna D, Abbate M, Benigni A: Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals. J Am Soc Nephrol 1999;10:1542–1549.
Rodriguez-Iturbe B, Quiroz Y, Nava M, Bonet L, Chavez M, Herrera-Acosta J, Johnson RJ, Pons HA: Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats. Am J Physiol Renal Physiol 2002;282:F191–F201.
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.