Role of p38(MAPK) in cell volume regulation of perfused rat liver.
In perfused rat liver, hypoosmotic exposure (225 mosmol/L) leads to a volume-regulatory decrease by release of K(+), Cl(-) and HCO(3)(-) through Ba(2+)-, DIDS- and quinidine-sensitive ion channels. The underlying signal transduction mechanisms, however, are unknown. As hypoosmotic hepatocyte swelling leads to a rapid activation of extracellular signal regulated kinases (Erks) and of p38(MAPK), the role of mitogen-activated protein kinases (MAPK) and PI-3-kinase in mediating the RVD in perfused rat liver was studied. The presence of the MEK inhibitor PD 098 059, which blocks the hypoosmotic activation of Erks, had no effect on the extent and time course of cell volume regulatory K(+) efflux. However, inhibitors of p38(MAPK) such as SB 203 580 and PD 169 316, but not their inactive analogue SB 202 474, significantly delayed and diminished the volume-regulatory K(+) efflux. Accordingly, in presence of these p38(MAPK) inhibitors, the hepatocytes remained in a more swollen state after completion of RVD. Inhibition of hypoosmotic Erk activation by pertussis or cholera toxin, erbstatin or genistein had no effect on RVD by hypoosmolarity. Likewise, neither inhibition of PI-3-kinase by wortmannin or LY 294 002 nor inhibition of S 6 phosphorylation by rapamycin nor protein kinase inhibition by H-7, H-89 or KT 5823 led to a significant change of RVD upon hypoosmolarity. The amount and time course of K(+) release by oxidative stress upon addition of t-BOOH or H(2)O(2) remained unaffected by inhibition of p38(MAPK) by SB 203 580, suggesting a specific inhibition of RVD-dependent K(+) release by this inhibitor. The findings suggest that swelling-induced activation of p38(MAPK), but not of Erks and PI-3-kinase, is involved in RVD in liver, whereas p38(MAPK) is apparently not involved in the net K(+) release induced by oxidative stress.
vom Dahl
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Div. of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-Universität, Düsseldorf, Germany. dahlv@uni-duesseldorf.de
Schliess
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Graf
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Häussinger
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D
D000818:Animals; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007038:Hypotonic Solutions / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010477:Perfusion; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D005419:Flavonoids; D007038:Hypotonic Solutions; D007093:Imidazoles; D015221:Potassium Channels; D011725:Pyridines; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D011188:Potassium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one