title: Hyperosmolality induced by betaine or urea stimulates endothelin synthesis by differential activation of ERK and p38 MAP kinase in MDCK cells.
abstract: We have previously shown that cultured porcine inner medullary collecting duct cells produce endothelin (ET) which suppressed arginine vasopressin (AVP)-induced cyclic adenosine monophosphate (cAMP) generation in an autocrine/paracrine feedback-like fashion. Moreover, hyperosmolality, e.g. induced by sodium chloride and urea, stimulated ET synthesis. Since others showed that hyperosmolality also activates mitogen-activated protein (MAP) kinases and that p38 MAP kinase facilitates cellular influx of betaine to protect the cell from high extracellular solute (urea) concentrations, we were tempted to investigate a potential interaction of MAP kinases with ET production in cultured MDCK cells in response to extracellular hyperosmolality induced by betaine and urea, respectively. Increased extracellular tonicity (602 +/- 8 vs. control of 323 +/- 3 mosmol/kg H(2)O) induced by betaine stimulated ERK and, more strongly, p38 kinase activity at 0.5-2 h of incubation with a rise in ET-1 synthesis to 1,713 +/- 68 vs. 378 +/- 51 fmol/mg protein/24 h under control conditions (p < 0.01). The p38 MAP kinase inhibitor SB203580 suppressed the rise in betaine-induced ET-1 synthesis by 91% to 494 +/- 38 fmol/mg protein/24 h, whereas the MEK/ERK inhibitor U0126 suppressed it moderately by 34%. Hypertonicity induced by urea moderately stimulated ERK but not p38 MAP kinase activity at 0.5-2 h and at 24-48 h and resulted in a modest rise in ET-1 synthesis to 681 +/- 61 fmol/mg protein/24 h (p < 0.05) which was significantly suppressed by U0126 to 484 +/- 16 fmol/mg protein/24 h. These results suggest that a functional interaction between the MAP kinases ERK and p38 MAP kinase and ET-1 synthesis is involved in betaine's protection of MDCK cells in vitro which may represent an in vivo mechanism of protection from hyperosmotic stress induced by high extracellular solute concentrations.
authors.affiliation: Renal Section, Medical Policlinic/Department of Medicine, University of Bonn, Germany. hkramer@uni-bonn.de
authors.forename: H J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: T
authors.initials: T
authors.lastname: Hashemi
authors.forename: A
authors.initials: A
authors.lastname: Bäcker
authors.forename: D
authors.initials: D
authors.lastname: Bokemeyer
mesh_terms: D000818:Animals; D001622:Betaine / Q000494:pharmacology*; D004285:Dogs; D019332:Endothelin-1 / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009994:Osmolar Concentration; D013997:Time Factors; D014508:Urea / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D001622:Betaine; D014508:Urea; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases