Mechanism of increased renal gene expression during metabolic acidosis

Increased renal catabolism of plasma glutamine during metabolic acidosis ge nerates two ammonium ions that are predominantly excreted in the urine. The y function as expendable cations that facilitate the excretion of acids. Fu rther catabolism of alpha -ketoglutarate yields two bicarbonate ions that a re transported into the venous blood to partially compensate for the acidos is. In rat kidney, this adaptation is sustained, in part, by the induction of multiple enzymes and various transport systems. The pH-responsive increa ses 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'-u ntranslated 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 z eta -crystallin/NADPH:quinone reductase with high affinity and specificity. Increased binding of this protein during acidosis may initiate the pH-resp onsive stabilization of the GA mRNA. In contrast, induction of PEPCK occurs at the transcriptional level. In LLC-PK1-FBPase(+) kidney cells, a decreas e in intracellular pH leads to activation of the p38 stress-activated prote in kinase and subsequent phosphorylation of transcription factor ATF-2. Thi s transcription factor binds to cAMP-response element 1 within the PEPCK pr omoter and may enhance its transcription during metabolic acidosis.