Mechanism of increased renal gene expression during metabolic acidosis.
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 alpha-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-PK(1)-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 zeta-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-PK(1)-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.
Curthoys
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Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA. ncurth@lamar.colostate.edu
Gstraunthaler
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D000138:Acidosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D006597:Fructose-Bisphosphatase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005972:Glutaminase / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D014158:Transcription, Genetic
D006597:Fructose-Bisphosphatase; D005972:Glutaminase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)