Curthoys, Norman P., and Gerhard Gstraunthaler. Mechanism of increased renal gene expression during metabolic acidosis. Am J Physiol Renal Physiol 281: F381-F390, 2001.-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

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... 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 3Ј-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-PK 1-FBPase ϩ 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-PK 1-fructose 1,6-bisphosphatase cells RENAL GLUTAMINE METABOLISM GLUTAMINE IS AN IMPORTANT metabolic fuel that is constitutively metabolized in liver (34), intestinal epithelium (55), lymphocytes (59), brain (48), and various transformed cells (9). In contrast, renal catabolism of glutamine is activated only during metabolic acidosis (77). During normal acid-base balance, the kidney extracts and metabolizes very little of plasma glutamine (75). The measured renal arteriovenous difference for plasma glutamine is normally Ͻ3% of arterial concentration. However, ϳ20% of plasma glutamine is filtered by the glomeruli and enters the lumen of the nephron. The filtered glutamine is reabsorbed primarily by the epithelial cells of the proximal convoluted tubule (72). It is initially transported across the apical brush-border membrane, and subsequently most of the recovered glutamine is returned to the blood via transport across the basolateral membrane. The specific transporters that are responsible for the transcellular flux of glutamine have not been identified. Utilization of the small fraction of extracted plasma glutamine requires its transport into the mitochondrial matrix, where glutamine is deamidated by glutamin-Address for reprint requests and other correspondence: N. P. Curthoys,