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1 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870; and 2 Department of Physiology, University of Innsbruck, A-6010 Innsbruck, Austria
Increased renal catabolism of plasma glutamine during metabolic
acidosis generates two ammonium ions that are predominantly excreted in
the urine. They function as expendable cations that facilitate the
excretion of acids. Further catabolism of 
-ketoglutarate yields two
bicarbonate ions that are transported into the venous blood to
partially compensate for the acidosis. In rat kidney, this adaptation
is sustained, in part, by the induction of multiple enzymes and various
transport systems. The pH-responsive increases in glutaminase (GA) and
phosphoenolpyruvate carboxykinase (PEPCK) mRNAs are
reproduced in LLC-PK1-fructose 1,6-bisphosphatase (FBPase) cells. The increase in GA activity results from stabilization of the GA
mRNA. The 3'-untranslated region of the GA mRNA contains a direct
repeat of an eight-base AU sequence that functions as a pH-response
element. This sequence binds 
-crystallin/NADPH:quinone reductase
with high affinity and specificity. Increased binding of this protein
during acidosis may initiate the pH-responsive stabilization of the GA
mRNA. In contrast, induction of PEPCK occurs at the transcriptional
level. In LLC-PK1-FBPase+ kidney cells, a
decrease in intracellular pH leads to activation of the p38
stress-activated protein kinase and subsequent phosphorylation of
transcription factor ATF-2. This transcription factor binds to
cAMP-response element 1 within the PEPCK promoter and may enhance its
transcription during metabolic acidosis.
glutamine metabolism; glutaminase; phosphoenolpyruvate carboxykinase; LLC-PK1-fructose 1,6-bisphosphatase cells
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