Background: The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats. Methods: Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 µg ·kg–1 ·h–1) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry. Results: Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 ± 18.7 vs. control 209.6 ± 27.0 mEq·min–1, p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 ± 26.4; p < 0.05) and reversed (231.5 ± 13.9; p < 0.05) by ANP-5 µg ·kg–1 ·h–1. Sodium overload increased the expression of: RANTES (38.4.3 ± 0.8 vs. 2.9 ± 0.6%, p < 0.001), transforming-growth-factor-β1 (35.3 ± 1.0 vs. 5.0 ± 0.7%, p < 0.001), α-smooth muscle actin (15.6 ± 0.7 vs. 3.1 ± 0.3%, p < 0.001), NF-ĸB (9.4 ± 1.3 to 2.2 ± 0.5 cells/mm2, p < 0.001), HIF-1α (38.2 ± 1.7 to 8.4 ± 0.8 cells/mm2, p < 0.001) and angiotensin II (35.9 ± 1.3 to 8.2 ± 0.5%, p < 0.001). ANP-5 µg ·kg–1 ·h–1 prevented and reversed inflammation: RANTES (9.2 ± 0.5 and 6.9 ± 0.7, p < 0.001); transforming growth factor-β1 (13.2 ± 0.7 and 10.2 ± 0.5, p < 0.001) and α-smooth muscle actin (4.1 ± 0.4 and 5.2 ± 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-ĸB (3.2 ± 0.4 and 2.8 ± 0.5, p < 0.001) and angiotensin II (8.2 ± 0.5 and 9.1 ± 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1α expression (8.4 ± 0.8 and 8.8 ± 0.7, p < 0.001). Conclusion: Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.

Keywords:
Atrial natriuretic peptide, Sodium overload, Angiotensin II
1.
Brezis M, Heyman SN, Epstein FH: Determinants of intrarenal oxygenation. II. Hemodynamic effects. Am J Physiol 1994;267:F1063–F1068.
2.
Sutton TA, Molitoris BA: Mechanisms of cellular injury in ischemic acute renal failure. Semin Nephrol 1998;18:490–497.
3.
Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, Clerici C: Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem 2004;279:14871–14878.
4.
Maxwell P: HIF-1: An oxygen response system with special relevance to the kidney. J Am Soc Nephrol 2003;14:2712–2722.
5.
Brezis M, Rosen S: Hypoxia of the renal medulla. Its implications for disease. N Engl J Med 1995;332:647–655.
6.
Manotham K, Tanaka T, Ohse T, Kojima I, Miyata T, Inagi R, Tanaka H, Sassa R, Fujita T, Nangaku M: A biologic role of HIF-1 in the renal medulla. Kidney Int 2005;67:1428–1439.
7.
Siragi HM: Angiotensin II compartmentalization within the kidney: effects of salt diet and blood pressure alterations. Curr Opin Nephrol Hypertens 2006;15:50–53.
8.
Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J: Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35:881–900.
9.
Li C, Sun BK, Lim SW, Song JC, Kang SW, Kim YS, Kang DH, Cha JH, Kim J, Yang CW: Combined effects of losartan and pravastatin on interstitial inflammation and fibrosis in chronic cyclosporine-induced nephropathy. Transplantation 2005;79:1522– 1529.
10.
Sun BK, Li C, Lim SW, Choi BS, Lee SH, Kim YS, Bang BK, Yang CW: Blockade of angiotensin II with losartan attenuates transforming growth factor-beta 1 inducible gene-h3 (betaig-h3) expression in a model of chronic cyclosporine nephrotoxicity. Nephron Exp Nephrol 2005;99:E9–E16.
11.
Pandey KN: Biology of natriuretic peptides and their receptors. Peptides 2005;26:901–932.
12.
Kiemer AK, Furst R, Vollmar AM: Vasoprotective actions of the atrial natriuretic peptide. Curr Med Chem Cardiovasc Hematol Agents 2005;3:11–21.
13.
Calderone A: Natriuretic peptides and the management of heart failure. Minerva Endocrinol 2004;29:113–127.
14.
Chen YF: Atrial natriuretic peptide in hypoxia. Peptides 2005;26:1068–1077.
15.
Kiemer AK, Weber NC, Vollmar AM: Induction of IkappaB: atrial natriuretic peptide as a regulator of the NF-kappaB pathway. Biochem Biophys Res Commun 2002;295:1068–1076.
16.
Vollmar AM: The role of atrial natriuretic peptide in the immune system. Peptides 2005;26:1086–1094.
17.
Chatterjee PK, Hawksworth GM, McLay JS: Cytokine-stimulated nitric oxide production in the human renal proximal tubule and its modulation by natriuretic peptides: a novel immunomodulatory mechanism? Exp Nephrol 1999;7:438–448.
18.
Roson MI, Cavallero S, Della Penna S: Acute sodium overload produces renal tubulointerstitial inflammation in normal rats. Kidney Int 2006;70:1439–1446.
19.
Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) immunoperoxidase techniques: a comparision between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577–580.
20.
Dunn BR, Ichikawa I, Pfeffer JM: Renal and systemic hemodynamic effects of synthetic atrial natriuretic peptide in the anesthetized rat. Circ Res 1986;59:237–246.
21.
Hirata Y, Ishii M, Sugimoto T, Matsuoka H, Sugimoto T, Kangawa K, Matsuo H: The effects of human atrial 28-amino acid peptide on systemic and renal hemodynamics in anesthetized rats. Circ Res 1985;57:634–639.
22.
Lassen NA, Munk O, Thaysen JH: Oxygen consumption and sodium reabsorption in the kidney. Acta Physiol Scand 1961;51:371–384.
23.
Lang RE, Tholken H, Ganten D, Luft FC, Ruskoaho H, Unger T: Atrial natriuretic factor; a circulating hormone stimulated by volume loading. Nature 1985;314:828–834.
24.
Klinger JR, Pietras L, Warburton R, Hill NS: Reduced oxygen tension increases atrial natriuretic peptide release from atrial cardiocytes. Exp Biol Med 2001;226:847–853.
25.
Chun YS, Hyun JY, Kwak YG, Kim IS, Kim CH, Choi E, Kim MS, Park JW: Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1. Biochem J 2003;370:149–157.
26.
Semenza GL: HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 2001;13:167–171.
27.
Epstein FH: Oxygen and renal metabolism. Kidney Int 1997;51:381–385.
28.
Sanjuan-Pla A, Cervera AM, Apostolova N, Garcia Bour R, Victor VM, Murphy MP, Mc Creath KJ: A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1alpha. FEBS Lett 2005;579:2669–2674.
29.
Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J: Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int 2002;82(suppl):12–22.
30.
Li N, Yi FX, Spurrier JL, Bobrowitz CA, Zou AP: Production of superoxide through NADH oxidase in thick ascending limb of Henle’s loop in rat kidney. Am J Physiol Renal Physiol 2002;282:F1111–F1119.
31.
Zou AP, Li N, Cowley AW: Production and actions of superoxide in renal medulla. Hypertension 2001;37:547–553.
32.
Rodriguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincon J, Chavez M, Parra G, Herrera-Acosta J, Gomez-Garre D, Largo R, Ejido J, Johnson RJ: Mycofenolate mofetil prevents salt-selsitive hypertension resulting from angiotensin II exposure. Kidney Int 2001;59:2222–2232.
33.
Beltowski J, Wójcicka G: Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research. Med Sci Monit 2002;8:RA39–RA52.
34.
Schreck R, Rieber P, Baeuerle PA: Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kB transcription factor and HIV. EMBO J 1991;10:2247–2258.
35.
Nishiyama A, Yoshizumi M, Rahman M, Kobori H, Seth DM, Miyatake A, Zhang GX, Yao L, Hitomi H, Shokoji T, Kiyomoyo H, Kimura S, Tamaki T, Kohono M, Abe Y: Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats. Kidney Int 2004;65:972–981.
36.
Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn AJ: Differential regulation of angiotensin levels in plasma and kidney of the rat. Hypertension 1991;18:763–773.
37.
Kiemer AK, Weber NC, Furst R, Bildner M, Kulhanek-Heinze S, Vollmar AM: Inhibition of p38 MAPK activation via induction of MKP-1: atrial natriuretic peptide reduces TNF-alpha-induced actin polymerization and endothelial permeability. Circ Res 2002;90:874–881.
38.
Kiemer AK, Lehner MD, Hartung T, Vollmar AM: Inhibition of cyclooxygenase-2 by natriuretic peptide. Endocrinology 2002;143:846–852.
39.
Kiemer AK, Vollmar AM: Autocrine regulation of inducible nitric-oxide synthase in macrophages by atrial natriuretic peptide. J Biol Chem 1998;273:13444–13451.
40.
Irwin DC, Tissot van Patot MC, Tucker A, Bower R: Direct ANP inhibition of hypoxia-induced inflammatory pathways in pulmonary microvascular and macrovascular endothelial monolayers. Am J Physiol Lung Cell Mol Physiol 2005;288:L849–L859.
© 2006 S. Karger AG, Basel
2007
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.