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2B-Adrenergic receptors activate MAPK and
modulate proliferation of primary cultured proximal tubule cells
Institut National de la Santé et de la Recherche Médicale 1 Unit 388 and 2 Unit 531, Institut L. Bugnard, Centre Hospitalier Universitaire Rangueil, 31403 Toulouse Cedex 4, France; and 3 Department of Pharmacology, School of Medicine, University of Patras, 26110 Rio Patras, Greece
In the rat
proximal tubule, the
2B-adrenergic receptor
(
2B-AR) enhances Na+ reabsorption by
increasing the activity of Na+/H+ exchanger
isoform NHE3. The mechanisms involved are unclear, and inhibition of
cAMP production remains controversial. In this study, we reinvestigated
2B-AR signaling pathways using rat proximal tubule cells
(PTC) in primary culture and LLC-PK1 cells permanently transfected with the RNG gene (rat nonglycosylated
2-AR). Binding experiments indicated that PTC express
substantial amounts of
2B-AR (130 fmol/mg protein), and
only RNG transcripts were detected. In both cell types, the
2B-AR is coupled to G protein, and its stimulation by
dexmedetomidine, but not by UK-14304, provoked a significant inhibition
of the accumulation of cAMP induced by forskolin or parathyroid
hormone. Exposure to
2-agonists increased arachidonic
acid release and caused extracellular signal-regulated kinase (ERK)1/2
phosphorylation, which correlated with enhanced mitogen-activated
protein kinse (MAPK) activity and nuclear translocation. MAPK
phosphorylation was blunted by pertussis toxin but not by protein
kinase C desensitization, and it coincided with transient phosphorylation of Shc. Finally, treatment with UK-14304 accelerated cell growth. Further studies will be necessary to clarify the precise
mechanism of MAPK activation, but the present data suggest that
2B-AR may play a positive role during tubular regeneration.
kidney; mitogen-activated protein kinase
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