In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction.

Wojtaszek, Paul A.; Heasley, Lynn E.; Berl, Tomás

doi:10.1172/jci4384

Cited by 27 publications

(22 citation statements)

References 28 publications

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“…In the present study, the level of phosphorylation of MAP kinases was taken as an index of their activation since only phosphorylated MAP kinases are active (5) and the increase in phosphorylation parallels the activity of MAP kinases in MTAL cells (30). Our results, taken together with a recent study showing that water restriction activates MAP kinases in the rat renal inner medulla (33), support the physiological relevance of the activation of MAP kinases by extracellular hypertonicity.…”

Section: Discussionsupporting

confidence: 78%

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

Roger

Martin

Rousselot

et al. 1999

Journal of Biological Chemistry

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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 NH 2 -terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a doseand 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.During diuresis and antidiuresis, the kidney medulla is exposed to large fluctuations of interstitial osmolarity (1), 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 (2, 3). 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 (4). The intracellular signaling pathways mediating these adaptive mechanisms, especially the role of MAP kinases, are still incompletely understood. Mitogen-activ...

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Section: Discussionsupporting

confidence: 78%

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

Roger

Martin

Rousselot

et al. 1999

Journal of Biological Chemistry

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“…It may reflect a response to osmotic stress as suggested by studies in which urea and sodium chloride induced hypertonic stress activate ERK in cultured inner medullary CD cells (19,20). This postulate is supported by studies in rats in which hypertonic stress caused by water restriction induced activation of ERK in the papilla (21), and by in vitro studies in which hypertonicity-induced transcription of AQP-1 in inner medullary CD cells operates, in part, via ERK (22).…”

Section: Discussionmentioning

confidence: 84%

Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies

Takao¹,

Stambe²,

Hill³

et al. 2004

Journal of the American Society of Nephrology

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“…Renal inner medullary cells are exposed to high levels of NaCl and urea, and those levels are changed associated with changes in urine concentration. Acute elevation of NaCl, but not of urea, activates p38 in mIMCD3 cells (5,10), and in vivo water restriction increases p38 activity in the renal medulla, where NaCl concentration increases, but not in the renal cortex, where it does not (36,37). Mammalian cells also accumulate protective organic osmolytes in response to hypertonicity.…”

Section: Discussionmentioning

confidence: 99%

Rapid activation of G ₂ /M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase

Dmitrieva

Bulavin

Fornace

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Cells in the kidney medulla are subject to variable and often extreme osmotic stress during concentration of the urine. Previous studies showed that renal inner medullary epithelial (IME) cells respond to hypertonicity by G 2 arrest. The purpose of the present study was to investigate the mechanisms involved in initiation and maintenance of G 2 arrest. Rapid initiation of G 2 arrest after UV radiation is mediated by p38 kinase. Here we find that p38 kinase is responsible for rapid initiation of the G 2 delay in IME cells after the hypertonic stress created by adding NaCl. High NaCl, but not high urea, rapidly initiates G2 arrest. Inhibition of p38 kinase by SB202190 (10 M) blocks the rapid initiation of this checkpoint both in an immortalized cell line (mIMCD3) and in second-passage IME cells from mouse renal inner medulla. p38 inhibition does not affect exit from G2 arrest. The rapid initiation of G2 arrest is followed by inhibition of cdc2 kinase, which is also prevented by SB202190. To assess the possible protective role of G2 arrest, we measured DNA strand breaks as reflected by immunostaining against phospho-histone H2AX, which becomes phosphorylated on Ser-139 associated with DNA breaks. Abrogation of rapid G 2͞M checkpoint activation by SB202190 increases the histone H2AX phosphorylation in G2͞M cells. We propose that the rapid initiation of G 2 delay by p38 kinase after hypertonicity protects the cells by decreasing the level of DNA breaks caused by aberrant mitosis entry.

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In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction.

Cited by 27 publications

References 28 publications

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

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

Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies

Rapid activation of G ₂ /M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase

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In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction.

Cited by 27 publications

References 28 publications

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

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

Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies

Rapid activation of G 2 /M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase

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Product

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Rapid activation of G ₂ /M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase