Cell Shrinkage Triggers the Activation of Mitogen-activated Protein Kinases by Hypertonicity in the Rat Kidney Medullary Thick Ascending Limb of the Henle's Loop

Abstract

The kidney medulla is exposed to very high interstitial osmolarity leading to the activation of mitogen-activated protein kinases (MAPK). However, the respective roles of increased intracellular osmolality and of cell shrinkage in MAPK activation are not known. Similarly, the participation of MAPK in the regulatory volume increase (RVI) following cell shrinkage remains to be investigated. In the rat medullary thick ascending limb of Henle (MTAL), extracellular hypertonicity produced by addition of NaCl or sucrose increased the phosphorylation level of extracellular signal-regulated kinase (ERK) and p38 kinase and to a lesser extent c-Jun NH2-terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a dose- and time-dependent manner. In contrast, hypertonic urea had no effect. The extent of MAPK activation was correlated with the extent of MTAL cellular volume decrease. Increasing intracellular osmolality without modifying cellular volume did not activate MAPK, whereas cell shrinkage without variation in osmolality activated both ERK and p38. In the presence of 600 mosmol/liter NaCl, the maximal cell shrinkage was observed after 10 min at 37 °C and the MTAL cellular volume was reduced to 70% of its initial value. Then, RVI occurred and the cellular volume progressively recovered to reach about 90% of its initial value after 30 min. SB203580, a specific inhibitor of p38, almost completely inhibited the cellular volume recovery, whereas inhibition of ERK did not alter RVI. In conclusion, in rat MTAL: 1) cell shrinkage, but not intracellular hyperosmolality, triggers the activation of both ERK and p38 kinase in response to extracellular hypertonicity; and 2) RVI is dependent on p38 kinase activation. The kidney medulla is exposed to very high interstitial osmolarity leading to the activation of mitogen-activated protein kinases (MAPK). However, the respective roles of increased intracellular osmolality and of cell shrinkage in MAPK activation are not known. Similarly, the participation of MAPK in the regulatory volume increase (RVI) following cell shrinkage remains to be investigated. In the rat medullary thick ascending limb of Henle (MTAL), extracellular hypertonicity produced by addition of NaCl or sucrose increased the phosphorylation level of extracellular signal-regulated kinase (ERK) and p38 kinase and to a lesser extent c-Jun NH2-terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a dose- and time-dependent manner. In contrast, hypertonic urea had no effect. The extent of MAPK activation was correlated with the extent of MTAL cellular volume decrease. Increasing intracellular osmolality without modifying cellular volume did not activate MAPK, whereas cell shrinkage without variation in osmolality activated both ERK and p38. In the presence of 600 mosmol/liter NaCl, the maximal cell shrinkage was observed after 10 min at 37 °C and the MTAL cellular volume was reduced to 70% of its initial value. Then, RVI occurred and the cellular volume progressively recovered to reach about 90% of its initial value after 30 min. SB203580, a specific inhibitor of p38, almost completely inhibited the cellular volume recovery, whereas inhibition of ERK did not alter RVI. In conclusion, in rat MTAL: 1) cell shrinkage, but not intracellular hyperosmolality, triggers the activation of both ERK and p38 kinase in response to extracellular hypertonicity; and 2) RVI is dependent on p38 kinase activation. medullary thick ascending limb of Henle [4-(2-aminoethyl)-benzenesulfonylfluoride)] bovine serum albumin extracellular signal-regulated kinase c-Jun NH2-terminal kinase polyacrylamide gel electrophoresis regulatory volume increase Tris-buffered saline mitogen-activated protein mitogen-activated protein kinase During diuresis and antidiuresis, the kidney medulla is exposed to large fluctuations of interstitial osmolarity (1Knepper M.A. Rector Jr., F.C. Brenner B.M. The Kidney. 5th Ed. W. B. Saunders Co., Philadelphia1996: 532-570Google Scholar), which challenge cell volume constancy. Cells of the medullary thick ascending limb of Henle (MTAL)1 are of special interest, since they are the major contributor to the generation of the renal cortico-papillary osmotic gradient allowing urinary concentration in terrestrial animals. The first adaptive process occurring in response to extracellular hypertonicity-induced cell shrinkage is a regulatory cell volume increase (RVI). The RVI results from the stimulation of ion transporters which increase the intracellular ion content within minutes and partially restore the cellular volume from the initial cell shrinkage (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar, 3Sun A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google Scholar). A second adaptive mechanism, in mammalian cells, is the induction of genes encoding proteins involved in the accumulation of intracellular “compatible osmolytes” within hours and days. These osmoprotective proteins are either enzymes,i.e. aldose reductase generating sorbitol from glucose, or organic osmolytes transporters, i.e. myo-inositol, taurine, glycerophosphocholine, and betaine (4Burg M.B. Am. J. Physiol. 1995; 268: F983-F996Crossref PubMed Google Scholar). The intracellular signaling pathways mediating these adaptive mechanisms, especially the role of MAP kinases, are still incompletely understood.Mitogen-activated protein (MAP) kinase cascades are important intracellular signal-transduction pathways activated in response to changes in osmolality. MAP kinases are serine/threonine kinases activated via a cascade of kinases involving a sequential phosphorylation of two kinases (MAP kinase kinase kinase and MAP kinase kinase), which activates a MAP kinase via a dual phosphorylation on threonine and tyrosine residues (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar). In mammalian cells, the MAP kinase family contains three major subgroups responding to distinct extracellular stimuli: extracellular signal-regulated kinases 1 and 2 (ERK) principally activated by growth factors, integrin-matrix interaction, and hormones or neurotransmitters with serpentine receptors (6Wu J. Dent P. Jelinek T. Wolfman A. Weber M.J. Sturgill T.W. Science. 1993; 262: 1065-1072Crossref PubMed Scopus (817) Google Scholar, 7Graves L.M. Bornfeldt K.E. Raines E.W. Potts B.C. MacDonald S.G. Ross R. Krebs E.G. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10300-10304Crossref PubMed Scopus (400) Google Scholar, 8Ferby I.M. Waga I. Sakanaka C. Kume K. Shimizu T. J. Biol. Chem. 1994; 269: 30485-30488Abstract Full Text PDF PubMed Google Scholar, 9Morino N. Mimura T. Hamasaki K. Tobe K. Ueki K. Kikuchi K. Takehara K. Kadowaki T. Yazaki Y. Nojima Y. J. Biol. Chem. 1995; 270: 269-273Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 10Flordellis C.S. Berguerand M. Gouache P. Barbu V. Gavras H. Handy D.E. Béréziat G. Masliah J. J. Biol. Chem. 1995; 270: 3491-3494Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 11Crespo P. Xu N. Simmonds W.S. Gutkind J.S. Nature. 1994; 369: 418-420Crossref PubMed Scopus (758) Google Scholar, 12Liao D.-F. Monia B. Dean N. Berk B.C. J. Biol. Chem. 1997; 272: 6146-6150Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar); c-Jun NH2-terminal kinases (JNK, also known as stress-activated protein kinases 1); and p38 kinases (also known as stress-activated protein kinases 2) activated by and hypertonic T. Biol. PubMed Scopus Google Scholar, S. J. J. 1994; Full Text PDF PubMed Scopus Google Scholar, T. B. Biol. 1994; PubMed Scopus Google Scholar, S. H. T. Y. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. Science. PubMed Scopus Google Scholar). the of MAP kinases to the of via phosphorylation of (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar, T. Biol. PubMed Scopus Google Scholar). However, of MAP kinases are activation of which and kinase H. R. R. Krebs E.G. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. D.E. J. Biol. Chem. 1995; 270: PubMed Scopus Google Scholar). In be involved in the of H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the p38 kinase be in and growth J. S. J. J. Biol. PubMed Scopus Google Scholar, T. K. K. M. H. Y. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and in the stimulation of by G. R. T. A. A. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google of the three of MAP kinases by extracellular hypertonicity in cell in C. M. Science. PubMed Scopus Google B. Science. 1994; 265: PubMed Scopus Google Scholar, T. A. A. K. T. N. Y. J. 1994; PubMed Scopus Google Scholar, Y. K. H. T. T. Y. Krebs E.G. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, Am. J. Physiol. Google Scholar, T. G. L.M. Am. J. Physiol. 1997; 272: Google Scholar), as as in rat MTAL Am. J. Physiol. Google Scholar), but the of activation by extracellular hypertonicity to be the respective role of intracellular cell shrinkage in the activation of MAP kinases by extracellular the the MAP kinase activation and the regulatory cell volume increase investigated. 1) to the of on the activation of MAP kinases in MTAL by and 2) to the MAP kinase activation and cell volume cell shrinkage by extracellular hypertonicity activates MAP kinases in rat In results the MAP kinases, p38 kinase to a major role in the cell response to extracellular i.e. the hypertonicity to activate MAP kinases in cell (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar), T. A. A. K. T. N. Y. J. 1994; PubMed Scopus Google Scholar, Y. K. H. T. T. Y. Krebs E.G. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, D. J. R. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google with mammalian and I.M. Waga I. Sakanaka C. Kume K. Shimizu T. J. Biol. Chem. 1994; 269: 30485-30488Abstract Full Text PDF PubMed Google Scholar, T. G. L.M. Am. J. Physiol. 1997; 272: Google Scholar, D. S. M.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with the results of Am. J. Physiol. Google Scholar), to rat MTAL cells, which are exposed to extracellular from to 600 mosmol/liter diuresis and antidiuresis, (1Knepper M.A. Rector Jr., F.C. Brenner B.M. The Kidney. 5th Ed. W. B. Saunders Co., Philadelphia1996: 532-570Google Scholar). In the the level of phosphorylation of MAP kinases was as of activation since MAP kinases are (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google and the increase in phosphorylation the of MAP kinases in MTAL Am. J. Physiol. Google Scholar). with a activates MAP kinases in the rat renal medulla T. J. PubMed Scopus Google Scholar), the of the activation of MAP kinases by extracellular major role of MTAL cell shrinkage in the hypertonicity-induced MAP kinases activation is by the following 1) which did not alter cellular did not activate MAP 2) hypertonic which a in cellular was a of ERK and p38 kinases hypertonic cellular volume was correlated with the activation level of ERK and p38 increased intracellular osmolarity without in cellular volume did not activate ERK and p38 and cell shrinkage was with activation of ERK and p38 which was to the initial cell These results cell shrinkage activates the MAP kinases in rat MTAL A role cell volume in the of cellular signaling pathways in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google activates MAP kinases changes in cellular the of the be the be extracellular hypertonicity the leading to increase in concentration of which the role of volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). of growth and receptors leading to activation to the activation of MAP kinases by hypertonicity via C. M. Science. PubMed Scopus Google Scholar). hypertonicity tyrosine phosphorylation of cellular proteins in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and in A. K. J. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and the activation of ERK and p38 kinase is tyrosine in rat MTAL Am. J. Physiol. Google both MTAL and are exposed to extracellular of the activation of MAP kinases a cellular In with Am. J. Physiol. Google Scholar), in MTAL cells, is not activated by hypertonic NaCl, in with the activation of by hypertonic NaCl in hypertonic sucrose by about in MTAL However, activation was stimulation of both ERK and p38 kinase activation level of MAP kinases be to the cell shrinkage by hypertonic sucrose as with hypertonic In MTAL cells, cell shrinkage a sequential activation of MAP kinases with a response of ERK and p38 kinase RVI is of cellular osmotic the initial cell shrinkage, MTAL a RVI response the activation of ion transporters A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google Scholar). process to the and the of the initial cell volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). results MTAL RVI after hypertonic challenge A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google with NaCl and and p38 kinase activation is ERK not to a p38 kinase activates ion transporters phosphorylation or remains to be a role a J. S. J. J. Biol. PubMed Scopus Google conclusion, in rat MTAL cells, hypertonic extracellular activates ERK and p38 kinase and in a lesser extent activation was not the of increase in intracellular but was by cell In activation of p38 kinase is in the regulatory cell volume increase a cell the of the rat kidney During diuresis and antidiuresis, the kidney medulla is exposed to large fluctuations of interstitial osmolarity (1Knepper M.A. Rector Jr., F.C. Brenner B.M. The Kidney. 5th Ed. W. B. Saunders Co., Philadelphia1996: 532-570Google Scholar), which challenge cell volume constancy. Cells of the medullary thick ascending limb of Henle (MTAL)1 are of special interest, since they are the major contributor to the generation of the renal cortico-papillary osmotic gradient allowing urinary concentration in terrestrial animals. The first adaptive process occurring in response to extracellular hypertonicity-induced cell shrinkage is a regulatory cell volume increase (RVI). The RVI results from the stimulation of ion transporters which increase the intracellular ion content within minutes and partially restore the cellular volume from the initial cell shrinkage (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar, 3Sun A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google Scholar). A second adaptive mechanism, in mammalian cells, is the induction of genes encoding proteins involved in the accumulation of intracellular “compatible osmolytes” within hours and days. These osmoprotective proteins are either enzymes,i.e. aldose reductase generating sorbitol from glucose, or organic osmolytes transporters, i.e. myo-inositol, taurine, glycerophosphocholine, and betaine (4Burg M.B. Am. J. Physiol. 1995; 268: F983-F996Crossref PubMed Google Scholar). The intracellular signaling pathways mediating these adaptive mechanisms, especially the role of MAP kinases, are still incompletely protein (MAP) kinase cascades are important intracellular signal-transduction pathways activated in response to changes in osmolality. MAP kinases are serine/threonine kinases activated via a cascade of kinases involving a sequential phosphorylation of two kinases (MAP kinase kinase kinase and MAP kinase kinase), which activates a MAP kinase via a dual phosphorylation on threonine and tyrosine residues (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar). In mammalian cells, the MAP kinase family contains three major subgroups responding to distinct extracellular stimuli: extracellular signal-regulated kinases 1 and 2 (ERK) principally activated by growth factors, integrin-matrix interaction, and hormones or neurotransmitters with serpentine receptors (6Wu J. Dent P. Jelinek T. Wolfman A. Weber M.J. Sturgill T.W. Science. 1993; 262: 1065-1072Crossref PubMed Scopus (817) Google Scholar, 7Graves L.M. Bornfeldt K.E. Raines E.W. Potts B.C. MacDonald S.G. Ross R. Krebs E.G. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10300-10304Crossref PubMed Scopus (400) Google Scholar, 8Ferby I.M. Waga I. Sakanaka C. Kume K. Shimizu T. J. Biol. Chem. 1994; 269: 30485-30488Abstract Full Text PDF PubMed Google Scholar, 9Morino N. Mimura T. Hamasaki K. Tobe K. Ueki K. Kikuchi K. Takehara K. Kadowaki T. Yazaki Y. Nojima Y. J. Biol. Chem. 1995; 270: 269-273Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 10Flordellis C.S. Berguerand M. Gouache P. Barbu V. Gavras H. Handy D.E. Béréziat G. Masliah J. J. Biol. Chem. 1995; 270: 3491-3494Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 11Crespo P. Xu N. Simmonds W.S. Gutkind J.S. Nature. 1994; 369: 418-420Crossref PubMed Scopus (758) Google Scholar, 12Liao D.-F. Monia B. Dean N. Berk B.C. J. Biol. Chem. 1997; 272: 6146-6150Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar); c-Jun NH2-terminal kinases (JNK, also known as stress-activated protein kinases 1); and p38 kinases (also known as stress-activated protein kinases 2) activated by and hypertonic T. Biol. PubMed Scopus Google Scholar, S. J. J. 1994; Full Text PDF PubMed Scopus Google Scholar, T. B. Biol. 1994; PubMed Scopus Google Scholar, S. H. T. Y. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. Science. PubMed Scopus Google Scholar). the of MAP kinases to the of via phosphorylation of (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar, T. Biol. PubMed Scopus Google Scholar). However, of MAP kinases are activation of which and kinase H. R. R. Krebs E.G. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. D.E. J. Biol. Chem. 1995; 270: PubMed Scopus Google Scholar). In be involved in the of H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the p38 kinase be in and growth J. S. J. J. Biol. PubMed Scopus Google Scholar, T. K. K. M. H. Y. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and in the stimulation of by G. R. T. A. A. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of the three of MAP kinases by extracellular hypertonicity in cell in C. M. Science. PubMed Scopus Google B. Science. 1994; 265: PubMed Scopus Google Scholar, T. A. A. K. T. N. Y. J. 1994; PubMed Scopus Google Scholar, Y. K. H. T. T. Y. Krebs E.G. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, Am. J. Physiol. Google Scholar, T. G. L.M. Am. J. Physiol. 1997; 272: Google Scholar), as as in rat MTAL Am. J. Physiol. Google Scholar), but the of activation by extracellular hypertonicity to be the respective role of intracellular cell shrinkage in the activation of MAP kinases by extracellular the the MAP kinase activation and the regulatory cell volume increase investigated. 1) to the of on the activation of MAP kinases in MTAL by and 2) to the MAP kinase activation and cell volume cell shrinkage by extracellular hypertonicity activates MAP kinases in rat In results the MAP kinases, p38 kinase to a major role in the cell response to extracellular i.e. the hypertonicity to activate MAP kinases in cell (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar), T. A. A. K. T. N. Y. J. 1994; PubMed Scopus Google Scholar, Y. K. H. T. T. Y. Krebs E.G. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, D. J. R. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google with mammalian and I.M. Waga I. Sakanaka C. Kume K. Shimizu T. J. Biol. Chem. 1994; 269: 30485-30488Abstract Full Text PDF PubMed Google Scholar, T. G. L.M. Am. J. Physiol. 1997; 272: Google Scholar, D. S. M.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with the results of Am. J. Physiol. Google Scholar), to rat MTAL cells, which are exposed to extracellular from to 600 mosmol/liter diuresis and antidiuresis, (1Knepper M.A. Rector Jr., F.C. Brenner B.M. The Kidney. 5th Ed. W. B. Saunders Co., Philadelphia1996: 532-570Google Scholar). In the the level of phosphorylation of MAP kinases was as of activation since MAP kinases are (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google and the increase in phosphorylation the of MAP kinases in MTAL Am. J. Physiol. Google Scholar). with a activates MAP kinases in the rat renal medulla T. J. PubMed Scopus Google Scholar), the of the activation of MAP kinases by extracellular major role of MTAL cell shrinkage in the hypertonicity-induced MAP kinases activation is by the following 1) which did not alter cellular did not activate MAP 2) hypertonic which a in cellular was a of ERK and p38 kinases hypertonic cellular volume was correlated with the activation level of ERK and p38 increased intracellular osmolarity without in cellular volume did not activate ERK and p38 and cell shrinkage was with activation of ERK and p38 which was to the initial cell These results cell shrinkage activates the MAP kinases in rat MTAL A role cell volume in the of cellular signaling pathways in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google activates MAP kinases changes in cellular the of the be the be extracellular hypertonicity the leading to increase in concentration of which the role of volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). of growth and receptors leading to activation to the activation of MAP kinases by hypertonicity via C. M. Science. PubMed Scopus Google Scholar). hypertonicity tyrosine phosphorylation of cellular proteins in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and in A. K. J. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and the activation of ERK and p38 kinase is tyrosine in rat MTAL Am. J. Physiol. Google both MTAL and are exposed to extracellular of the activation of MAP kinases a cellular In with Am. J. Physiol. Google Scholar), in MTAL cells, is not activated by hypertonic NaCl, in with the activation of by hypertonic NaCl in hypertonic sucrose by about in MTAL However, activation was stimulation of both ERK and p38 kinase activation level of MAP kinases be to the cell shrinkage by hypertonic sucrose as with hypertonic In MTAL cells, cell shrinkage a sequential activation of MAP kinases with a response of ERK and p38 kinase RVI is of cellular osmotic the initial cell shrinkage, MTAL a RVI response the activation of ion transporters A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google Scholar). process to the and the of the initial cell volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). results MTAL RVI after hypertonic challenge A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google with NaCl and and p38 kinase activation is ERK not to a p38 kinase activates ion transporters phosphorylation or remains to be a role a J. S. J. J. Biol. PubMed Scopus Google conclusion, in rat MTAL cells, hypertonic extracellular activates ERK and p38 kinase and in a lesser extent activation was not the of increase in intracellular but was by cell In activation of p38 kinase is in the regulatory cell volume increase a cell the of the rat kidney The cell shrinkage by extracellular hypertonicity activates MAP kinases in rat In results the MAP kinases, p38 kinase to a major role in the cell response to extracellular i.e. the RVI. hypertonicity to activate MAP kinases in cell (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar), T. A. A. K. T. N. Y. J. 1994; PubMed Scopus Google Scholar, Y. K. H. T. T. Y. Krebs E.G. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, D. J. R. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google with mammalian and I.M. Waga I. Sakanaka C. Kume K. Shimizu T. J. Biol. Chem. 1994; 269: 30485-30488Abstract Full Text PDF PubMed Google Scholar, T. G. L.M. Am. J. Physiol. 1997; 272: Google Scholar, D. S. M.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with the results of Am. J. Physiol. Google Scholar), to rat MTAL cells, which are exposed to extracellular from to 600 mosmol/liter diuresis and antidiuresis, (1Knepper M.A. Rector Jr., F.C. Brenner B.M. The Kidney. 5th Ed. W. B. Saunders Co., Philadelphia1996: 532-570Google Scholar). In the the level of phosphorylation of MAP kinases was as of activation since MAP kinases are (5Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google and the increase in phosphorylation the of MAP kinases in MTAL Am. J. Physiol. Google Scholar). with a activates MAP kinases in the rat renal medulla T. J. PubMed Scopus Google Scholar), the of the activation of MAP kinases by extracellular The major role of MTAL cell shrinkage in the hypertonicity-induced MAP kinases activation is by the following 1) which did not alter cellular did not activate MAP 2) hypertonic which a in cellular was a of ERK and p38 kinases hypertonic cellular volume was correlated with the activation level of ERK and p38 increased intracellular osmolarity without in cellular volume did not activate ERK and p38 and cell shrinkage was with activation of ERK and p38 which was to the initial cell These results cell shrinkage activates the MAP kinases in rat MTAL A role cell volume in the of cellular signaling pathways in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). activates MAP kinases changes in cellular the of the be the be extracellular hypertonicity the leading to increase in concentration of which the role of volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). of growth and receptors leading to activation to the activation of MAP kinases by hypertonicity via C. M. Science. PubMed Scopus Google Scholar). hypertonicity tyrosine phosphorylation of cellular proteins in K. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and in A. K. J. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and the activation of ERK and p38 kinase is tyrosine in rat MTAL Am. J. Physiol. Google Scholar). both MTAL and are exposed to extracellular of the activation of MAP kinases a cellular In with Am. J. Physiol. Google Scholar), in MTAL cells, is not activated by hypertonic NaCl, in with the activation of by hypertonic NaCl in hypertonic sucrose by about in MTAL However, activation was stimulation of both ERK and p38 kinase activation level of MAP kinases be to the cell shrinkage by hypertonic sucrose as with hypertonic In MTAL cells, cell shrinkage a sequential activation of MAP kinases with a response of ERK and p38 kinase The RVI is of cellular osmotic the initial cell shrinkage, MTAL a RVI response the activation of ion transporters A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google Scholar). process to the and the of the initial cell volume (2Parker J.C. Am. J. Physiol. 1993; 265: C1191-C1200Crossref PubMed Google Scholar). results MTAL RVI after hypertonic challenge A.M. Saltzberg S.N. Kikeri D. Hebert S.C. Kidney Int. 1990; 38: 1019-1029Abstract Full Text PDF PubMed Scopus (28) Google with NaCl and and p38 kinase activation is ERK not to a p38 kinase activates ion transporters phosphorylation or remains to be a role a J. S. J. J. Biol. PubMed Scopus Google Scholar). In conclusion, in rat MTAL cells, hypertonic extracellular activates ERK and p38 kinase and in a lesser extent activation was not the of increase in intracellular but was by cell In activation of p38 kinase is in the regulatory cell volume increase a cell the of the rat kidney S. of the