When the renal medulla becomes hypertonic in association with the formation of concentrated urine, the cells of the medulla avoid the stress of high intracellular salts by accumulating small non-perturbing organic osmolytes. The response has been studied in most detail in cultured kidney-derived cells, and confirmed in studies of the intact kidney. The non-perturbing osmolytes, myo-inositol, betaine, and sorbitol, are accumulated because of stimulation of the transcription of the genes for the proteins that catalyze their accumulation by transport or synthesis. The genes involved have all been cloned and sequenced and contain tonicity responsive regulatory elements (TonEs) in their 5′ region. During hypertonicity, the elements are occupied by TonE-binding protein, a transacting factor that has been cloned and characterized. Current efforts focus on identifying the mechanism by which cells sense hypertonicity and how that leads to activation of TonE-binding protein.

Keywords:
Myo-inositol, Betaine, Sorbitol, Tonicity responsive element, Stress
1.
Yancey PH, Clark ME, Hand SC, Bowlus RD, Somero GN: Living with water stress: Evolution of osmolyte system. Science 1982;217:1214–1222.
2.
Cohen DM: Mitogen-activated protein kinase cascades and the signaling of hyperosmotic stress to immediate early genes. Comp Biochem Physiol [A] 1997;117:291–299.
3.
Yancey PH, Burg MB: Distribution of major organic osmolytes in rabbit kidneys in diuresis and antidiuresis. Am J Physiol 1989;257:F602–F607.
4.
Sone M, Ohno A, Albrecht GJ, Thurau K, Beck F-X: Restoration of urine concentrating ability and accumulation of medullary osmolytes after chronic diuresis. Am J Physiol 1995;264:F480–F490.
5.
Hager K, Hazama A, Kwon HM, Loo DDF, Handler JS, Wright EM: Kinetics and specificity of the renal Na+ myo-inositol cotransporter expressed in Xenopus oocytes. J Membr Biol 1995;143:103–113.
6.
Matskevitch I, Wagner CA, Stegen C, Broer S, Noll B, Risler T, Kwon HM, Handler JS, Waldegger S, Busch AE, Lang F: Functional characterization of the betaine/γ-aminobutyric acid transporter BGT-1 expressed in Xenopus oocytes. J Biol Chem 1999;274:16709–16716.
7.
Horio M, Yamauchi A, Moriyama T, Imai E, Orita Y: Osmotic regulation of amino acids and system A transport in Madin-Darby canine kidney cells. Am J Physiol 1997;272:C804–C809.
8.
Yamauchi A, Uchida S, Preston AS, Kwon HM, Handler JS: Hypertonicity stimulates transcription of gene for Na+-myo-inositol cotransporter in MDCK cells. Am J Physiol 1993;264:F20–F23.
9.
Uchida S, Yamauchi A, Preston AS, Kwon HM, Handler JS: Medium tonicity regulates expression of the Na+- and Cl–-dependent betaine transporter in MDCK cells by increasing transcription of the transporter gene. J Clin Invest 1993;91:1604–1607.
10.
Smardo FL Jr, Burg MB, García-Perez A: Kidney aldose reductase gene transcription is osmotically regulated. Am J Physiol 1992;262:C776–C782.
11.
Cowley BD Jr, Ferraris JD, Carper D, Burg MB: In vivo osmoregulation of aldose reductase mRNA, protein, and sorbitol in renal medulla. Am J Physiol 1990;258:F154–F161.
12.
Kwon ED, Zablocki K, Jung KY, Peters EM, García-Perez A, Burg MB: Osmoregulation of GPC:choline phosphodiesterase in MDCK cells: Different effects of urea and NaCl. Am J Physiol 1995;269:C35–C41.
13.
Krump E, Nikitas K, Grinstein S: Induction of tyrosine phosphorylation and Na+/H+ exchanger activation during shrinkage of human neutrophils. J Biol Chem 1997;272:17303–17311.
14.
Cohen DM, Wasserman JC, Gullans SR: Immediate early gene and HSP70 expression in hyperosmotic stress in MDCK cells. Am J Physiol 1991;261:C594–C601.
15.
Kultz D, Madhany S, Burg MB: Hyperosmolality causes growth arrest of murine kidney cells: Induction of GADD45 and GADD153 by osmosensing via stress-activated Protein kinase 2. J Biol Chem 1998;273:13645–13651.
16.
Albertyn J, Hohmann S, Thevelein JM, Prior BA: GPD1, which encodes glycerol-3-phosphate dehydrogenase, is essential for growth under osmotic stress in Saccharomyces cerevisiae, and its expression is regulated by the high-osmolarity glycerol response pathway. Mol Cell Biol 1994;14:4135–4144.
17.
Itoh T, Yamauchi A, Miyai A, Yokoyama K, Kamada T, Ueda N, Fujiwara Y: Mitogen-activated protein kinase and its activator are regulated by hypertonic stress in Madin-Darby canine kidney cells. J Clin Invest 1994;93:2387–2392.
18.
Galcheva-Gargova Z, Derijard B, Wu I-H, Davis RJ: An osmosensing signal transduction pathway in mammalian cells. Science 1996;265:806–808.
19.
Han J, Lee J-D, Bibbs L, Ulevitch J: A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 1994;265:808–811.
20.
Wojtaszek PA, Heasley LE, Berl T: In vivo regulation of MAP kinases in Rattus norvegicus renal papilla by water loading and restriction. J Clin Invest 1999;102:1874–1881.
21.
Kwon HM, Itoh T, Rim JS, Handler JS: The MAP kinase cascade is not essential for transcriptional stimulation of osmolyte transporter genes. Biochem Biophys Res Commun 1995;213:975–979.
22.
Kultz D, Garcia-Perez A, Ferraris JD, Burg M: Distinct regulation of osmoprotective genes in yeast and mammals. J Biol Chem 1997;272:13165–13170.
23.
Sheikh-Hamad D, Di Mari J, Suki WN, Safirstein R, Watts BA III, Rouse D: p38 kinase activity is essential for osmotic induction of mRNAs for HSP70 and transporter for organic solute betaine in Madin-Darby canine kidney cells. J Biol Chem 1998;273:1832–1837.
24.
Denkert C, Warskulat U, Hensel F, Haussinger D: Osmolyte strategy in human monocytes and macrophages: Involvement of p38MAPK in hyperosmotic induction of betaine and myoinositol transporters. Arch Biochem Biophys 1998;354:172–180.
25.
Uchida S, García-Perez A, Murphy H, Burg MB: Signal for induction of aldose reductase in renal medullary cells by high external NaCl. Am J Physiol 1989;256:C614–C620.
26.
Burg M, Kwon ED, Kultz D: Regulation of gene expression by hypertonicity. Annu Rev Physiol 1997;59:437–455.
27.
Moriyama T, García-Perez A, Burg MB: Osmotic regulation of aldose reductase protein synthesis in renal medullary cells. J Biol Chem 1989;264:16810–16814.
28.
Takenaka M, Preston AS, Kwon HM, Handler J: The tonicity-sensitive element that mediates increased transcription of the betaine transporter gene in response to hypertonic stress. J Biol Chem 1994;269:29379–29381.
29.
Ferraris JD, Williams CK, Ohtaka A, García-Perez A: Functional consensus for mammalian osmotic response elements. Am J Physiol 1999;276:C667–C673.
30.
Miyakawa H, Woo SK, Chen C-P, Dahl SC, Handler JS, Kwon HM: Cis- and trans-acting factors regulating transcription of the BGT1 gene in response to hypertonicity. Am J Physiol 1998;274:F753–F761.
31.
Rim JS, Atta MG, Dahl SC, Berry GT, Handler JS, Kwon HM: Transcription of the sodium/myo-inositol cotransporter gene is regulated by multiple tonicity-responsive enhancers spread over 50 kilobase pairs in the 5′-flanking region. J Biol Chem 1998;273:20615–20621.
32.
Miyakawa H, Rim JS, Handler JS, Kwon HM: Identification of the second tonicity-responsive enhancer for the BGT1 gene. Biochim Biophys Acta 1999;1446:359–364.
33.
Ko BCB, Chung SM: Identification and characterization of multiple osmotic response sequences in the human aldose reductase gene. J Biol Chem 1997;272:16431–16437.
34.
Kaneko T, Takenaka M, Okabe M, Yoshimura Y, Yamauchi A, Horio M, Kwon HM, Handler JS, Imai E: Osmolarity in renal medulla of transgenic mice regulates transcription via 5′-flanking region of a canine BGT1 gene. Am J Physiol 1997;272:F610–F616.
35.
Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM: Tonicity-responsive enhancer binding protein: A Rel-like protein that stimulates transcription in response to hypertonicity. Proc Natl Acad Sci USA 1999;96:2538–2542.
36.
Atta MG, Dahl SC, Kwon HM, Handler JS: Tyrosine kinase inhibitors and immunosuppresants perturb the myo-inositol but not the betaine cotransporter in isotonic and hypertonic MDCK cells. Kidney Int 1999;55:956–962.
37.
Kirk K, Strange K: Functional properties and physiological roles of organic solute channels. Ann Rev Physiol 1998;60:719–736
38.
O’Neill WC: Physiological significance of volume-regulatory transporters. Am J Physiol 1999;276:C995–C1011.
© 2001 S. Karger AG, Basel
2001
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.