Curthoys N P
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA.
J Nutr. 2001 Sep;131(9 Suppl):2491S-5S; discussion 2496S-7S. doi: 10.1093/jn/131.9.2491S.
During normal acid-base balance, the kidney extracts very little of the plasma glutamine. However, during metabolic acidosis, as much as one third of the plasma glutamine is extracted and metabolized in a single pass through this organ. The substantial increase in renal utilization occurs solely within the proximal convoluted tubule and is sustained by compensating adaptations in the intraorgan metabolism of glutamine. The primary pathway for renal glutamine metabolism involves its transport into mitochondria and its deamidation and deamination by glutaminase (GA) and glutamate dehydrogenase (GDH), respectively. The resulting ammonium ions are excreted predominantly in the urine where they function as expendable cations to facilitate the excretion of acids. The resulting alpha-ketoglutarate is further metabolized to phosphoenolpyruvate and subsequently to glucose or CO2. The intermediate steps yield two bicarbonate ions that are selectively transported into the venous blood to partially compensate the metabolic acidosis. In rat kidney, this adaptation is sustained in part by the cell-specific induction of the glutaminase that results primarily from stabilization of the GA mRNA. The 3'-nontranslated region of the GA mRNA contains a direct repeat of an 8-base AU-sequence that functions as a pH-response element. This sequence exhibits a high affinity and specificity for zeta (z)-crystallin. The same protein binds to two separate, but homologous, 8-base AU-sequences within the 3'-nontranslated region of the GDH mRNA. The apparent binding activity of z-crystallin is increased significantly during onset of metabolic acidosis. Thus, increased binding of z-crystallin may initiate the pH-responsive stabilization of the two mRNAs.
在正常酸碱平衡状态下，肾脏仅摄取极少量的血浆谷氨酰胺。然而，在代谢性酸中毒时，多达三分之一的血浆谷氨酰胺在单次流经该器官时被摄取并代谢。肾脏利用率的显著增加仅发生在近端曲管内，并通过谷氨酰胺器官内代谢的代偿性适应得以维持。肾脏谷氨酰胺代谢的主要途径包括将其转运至线粒体，然后分别由谷氨酰胺酶（GA）和谷氨酸脱氢酶（GDH）进行脱酰胺和脱氨基作用。产生的铵离子主要经尿液排出，在尿液中作为可消耗的阳离子，促进酸的排泄。产生的α-酮戊二酸进一步代谢为磷酸烯醇丙酮酸，随后转化为葡萄糖或二氧化碳。中间步骤产生两个碳酸氢根离子，它们被选择性地转运至静脉血中，以部分代偿代谢性酸中毒。在大鼠肾脏中，这种适应性变化部分是由谷氨酰胺酶的细胞特异性诱导维持的，这主要源于GA mRNA的稳定。GA mRNA的3'-非翻译区包含一个8碱基AU序列的直接重复，其作为pH反应元件发挥作用。该序列对ζ（z）-晶状体蛋白表现出高亲和力和特异性。同一蛋白与GDH mRNA的3'-非翻译区内两个独立但同源的8碱基AU序列结合。在代谢性酸中毒发作期间，z-晶状体蛋白的表观结合活性显著增加。因此，z-晶状体蛋白结合增加可能启动这两种mRNA的pH反应性稳定。
