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1 Department of Physiology, University of Innsbruck, A-6010 Innsbruck, Austria; and 2 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523 - 1870
LLC-PK1-FBPase+
cells are a gluconeogenic and pH-responsive renal proximal tubule-like
cell line. On incubation with acidic medium (pH 6.9),
LLC-PK1-FBPase+ cells exhibit an increased rate
of ammonia production as well as increases in glutaminase and
phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels and
enzyme activities. The increase in PEPCK mRNA is due to an enhanced
rate of transcription that is initiated in response to intracellular
acidosis. The involvement of known MAPK activities (ERK1/2, SAPK/JNK,
p38) in the associated signal transduction pathway was examined by
determining the effects of specific MAPK activators and inhibitors on
basal and acid-induced PEPCK mRNA levels. Transfer of
LLC-PK1-FBPase+ cultures to acidic medium
resulted in specific phosphorylation, and thus activation, of p38 and
of activating transcription factor-2 (ATF-2), respectively. Anisomycin
(AI), a strong p38 activator, increased PEPCK mRNA to levels comparable
to those observed with acid stimulation. AI also induced a
time-dependent phosphorylation of p38 and ATF-2. SB-203580, a specific
p38 inhibitor, blocked both acid- and AI-induced PEPCK mRNA levels.
Western blot analyses revealed that the SB-203580-sensitive p38
isoform is strongly expressed. The octanucleotide sequence of the
cAMP-response element-1 site of the PEPCK promotor is a perfect match
to the consensus element for binding ATF-2. The specificity of ATF-2
binding was proven by ELISA. We conclude that the SB-203580-sensitive
p38-ATF-2 signaling pathway is a likely mediator of the
pH-responsive induction of PEPCK mRNA levels in renal
LLC-PK1-FBPase+ cells.
metabolic acidosis; proximal tubule; ammoniagenesis; gluconeogenesis; mitogen-activated protein kinase; fructose 1,6-bisphosphatase; phosphoenolpyruvate carboxykinase
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