Background/Aim: Endothelin-converting enzyme (ECE) catalyzes the generation of endothelin-1 (ET-1) from its inactive precursor big-ET-1. Previous studies suggested that the ET-1 system is involved in the regulation of sodium excretion by the kidney. In particular, ET-1 via the ETB receptor-mediated signaling has been shown to increase renal medullary blood flow and decrease sodium transport in the collecting duct, both acting to promote renal sodium excretion. The present study was designed to evaluate the possibility that alterations in dietary salt intake may regulate the ECE-1. Methods: Wistar rats were fed for 3 days either with a diet containing low salt (0.01% NaCl), normal salt (0.5% NaCl), or high salt intake, either by high salt diet (4% NaCl) or normal salt diet plus 0.9% saline drinking. The expression of and immunoreactive protein levels of ECE-1 in the renal medulla was studied by RT-PCR, Northern blotting and Western blotting techniques. Results: The expression of ECE-1 mRNA (by RT-PCR and Northern blotting), as well as the immunoreactive levels of ECE-1, were significantly higher in the renal medulla of rats exposed to high salt intake than in rats on normal salt diet. Conclusion: The findings suggest that upregulation of ECE-1, leading to increased generation of ET-1 in the renal medulla, may be a compensatory mechanism promoting enhanced sodium excretion by the kidney in response to high salt intake.

Keywords:
Endothelin, Endothelin-converting enzyme, Salt balance, Natriuresis, Renal medulla, Rats, high/low salt intake
1.
Kohan DE: Endothelins in the normal and diseased kidney. Am J Kidney Dis 1997;29:2–26.
2.
Opgenorth TJ, Wu-Wong JR, Shiosaki K: Endothelin-converting enzymes. FASEB J 1992;6:2653–2659.
3.
Turner AJ, Barnes K, Schweizer A, Valdenaire O: Isoforms of endothelin-converting enzyme: Why and where? Trends Pharmacol Sci 1998;19:483–486.
4.
Xu D, Emoto N, Giaid A, Slaughter C, Kaw S, deWit D, Yanagisawa M: ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 1994;78:473–485.
5.
Shimada K, Takahashi M, Tanzawa K: Cloning and functional expression of endothelin-converting enzyme from rat endothelial cells. J Biol Chem 1994;269:18275–18278.
6.
Emoto N, Yanagisawa M: Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J Biol Chem 1995;270:15262–15268.
7.
Barnes K, Turner AJ: The endothelin system and endothelin-converting enzyme in the brain: Molecular and cellular studies. Neurochem Res 1997;22:1033–1040.
8.
Pupilli C, Romagnani P, Lasagni L, Bellini F, Misciglia N, Emoto N, Yanagisawa M, Rizzo M, Mannelli M, Serio M: Localization of endothelin-converting enzyme-1 in human kidney. Am J Physiol 1997;273:F749–F756.
9.
Kotelevtsev Y, Webb DJ: Endothelin as a natriuretic hormone: The case for a paracrine action mediated by nitric oxide. Cardiovasc Res 2001;51:481–488.
10.
Abassi ZA, Ellahham S, Winaver J, Hoffman A: The intrarenal endothelin system and hypertension. News Physiol Sci 2001;16:152–156.
11.
Hoffman A, Abassi ZA, Brodsky S, Ramadan R, Winaver J: Mechanisms of big endothelin-1-induced diuresis and natriuresis: Role of ETB receptors. Hypertension 2000;35:732–739.
12.
Ohuchi T, Yanagisawa M, Gariepy CE: Renal tubular effects of endothelin-B receptor signaling: Its role in cardiovascular homeostasis and extracellular volume regulation. Curr Opin Nephrol Hypertens 2000;9:435–439.
13.
Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M: Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin Invest 2000;105:925–933.
14.
Pollock DM, Pollock JS: Evidence for endothelin involvement in the response to high salt. Am J Physiol Renal Physiol 2001;281:F144–F150.
15.
Hsieh TJ, Lin SR, Lee YJ, Shin SJ, Lai YH, Hsu CH, Tsai JH: Increased renal medullary endothelin-1 synthesis in prehypertensive DOCA- and salt-treated rats. Am J Physiol Renal Physiol 2000;279:F112–F121.
16.
Pollock DM, Allcock GH, Krishnan A, Dayton BD, Pollock JS: Upregulation of endothelin B receptors in kidneys of DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 2000;278:F279–F286.
17.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
18.
Abassi Z, Winaver J, Rubinstein I, Shimada K, Takahashi M, Tanzawa K, Hoffman A: Renal endothelin-converting enzyme in rats with congestive heart failure. J Cardiovasc Pharmacol 1998;31(suppl 1):31–34.
19.
Ikeda T, Ohta H, Okada M, Kawai N, Nakao R, Siegl PK, Kobayashi T, Maeda S, Miyauchi T, Nishikibe M: Pathophysiological roles of endothelin-1 in Dahl salt-sensitive hypertension. Hypertension 1999;34:514–519.
20.
Kitamura K, Tanaka T, Kato J, Ogawa T, Eto T, Tanaka K: Immunoreactive endothelin in rat kidney inner medulla: Marked decrease in spontaneously hypertensive rats. Biochem Biophys Res Commun 1989;162:38–44.
21.
Gellai M, DeWolf R, Pullen M, Nambi P: Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats. Kidney Int 1994;46:1287–1294.
22.
Roman RJ, Zou AP: Influence of the renal medullary circulation on the control of sodium excretion. Am J Physiol 1993;265:R963–R973.
23.
Cowley AW Jr: Role of the renal medulla in volume and arterial pressure regulation. Am J Physiol 1997;273:R1–R15.
24.
Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal NO production in the regulation of medullary blood flow. Am J Physiol 2003;284:R1355–R1369.
25.
Mattson DL, Lu S, Cowley AW Jr: Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol 1997;24:587–590.
26.
Majid DS, Navar LG: Nitric oxide in the control of renal hemodynamics and excretory function. Am J Hypertens 2001;14:74S–82S.
27.
Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J: Differential regulation of renal regional blood flow by endothelin-1. Am J Physiol 1996;271:F1166–F1172.
28.
Vassileva I, Mountain C, Pollock DM: Functional role of ETB receptors in the renal medulla. Hypertension 2003;41:1359–1363.
29.
Gallego MS, Ling BN: Regulation of amiloride-sensitive Na+ channels by endothelin-1 in distal nephron cells. Am J Physiol 1996;271:F451–F460.
30.
Ingelfinger JR, Pratt RE, Ellison K, Dzau VJ: Sodium regulation of angiotensinogen mRNA expression in rat kidney cortex and medulla. J Clin Invest 1986;78:1311–1315.
31.
El Dahr S, Yosipiv IV, Muchant DG, Chevalier RL: Salt intake modulates the developmental expression of renal kallikrein and bradykinin B2 receptors. Am J Physiol 1996;270:F425–F431.
32.
Hoffman A, Grossman E, Goldstein DS, Gill JR Jr, Keiser HR: Urinary excretion rate of endothelin-1 in patients with essential hypertension and salt sensitivity. Kidney Int 1994;45:556–560.
© 2004 S. Karger AG, Basel
2004
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.