Inhibition of glutamine synthetase in the mouse kidney - A novel mechanism of adaptation to metabolic acidosis
Inhibition of glutamine synthetase in the mouse kidney - A novel mechanism of adaptation to metabolic acidosis
复制标题
DOI：
10.1074/jbc.m302885200
复制
发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Baverel, G
中科院分区：
文献类型：
--
作者：
Conjard, A;Komaty, O;Baverel, G
作为小鼠肾氨生成调控研究的一部分，我们研究了慢性代谢性酸中毒对离体小鼠肾近端小管谷氨酰胺合成的影响。结果显示，在对照小鼠的小管中，谷氨酸和脯氨酸的谷氨酰胺合成率很高，鸟氨酸、丙氨酸和天冬氨酸的谷氨酰胺合成率较低。48小时后，代谢性酸中毒引起谷氨酰胺合成的明显抑制，从接近生理浓度的丙氨酸和脯氨酸被小管大量代谢；代谢性酸中毒也极大地刺激了谷氨酰胺的利用和代谢。这些影响伴随着(i)丙氨酸、脯氨酸和谷氨酰胺糖异生的大量增加和（ii）脯氨酸和谷氨酰胺的氨积累。酸性小鼠肾皮质磷酸烯醇丙酮酸羧激酶活性升高4倍，谷氨酸脱氢酶活性无明显变化；与已知的大鼠肾皮质相反，代谢性酸中毒显著降低小鼠肾皮质谷氨酰胺合成酶活性和蛋白水平，但不降低谷氨酰胺合成酶mRNA水平。这些结果强烈提示，在小鼠肾脏中，谷氨酰胺合成酶是一个重要的调节氨离子可用性的成分，以维持全身酸碱平衡。此外，他们表明，在啮齿动物中，肾谷氨酰胺合成酶的调节是物种特异性的。
As part of a study on the regulation of renal ammonia-genesis in the mouse kidney, we investigated the effect of chronic metabolic acidosis on glutamine synthesis by isolated mouse renal proximal tubules. The results obtained reveal that, in tubules from control mice, glutamine synthesis occurred at high rates from glutamate and proline and, to a lesser extent, from ornithine, alanine, and aspartate. A 48 h, metabolic acidosis caused a marked inhibition of glutamine synthesis from near-physiological concentrations of both alanine and proline that were avidly metabolized by the tubules; metabolic acidosis also greatly stimulated glutamine utilization and metabolism. These effects were accompanied by a large increase (i) in alanine, proline, and glutamine gluconeogenesis and (ii) in ammonia accumulation from proline and glutamine. In the renal cortex of acidotic mice, the activity of phosphoenolpyruvate carboxykinase increased 4-fold, but that of glutamate dehydrogenase did not change; in contrast with what is known in the rat renal cortex, metabolic acidosis markedly diminished the glutamine synthetase activity and protein level, but not the glutamine synthetase mRNA level in the mouse renal cortex. These results strongly suggest that, in the mouse kidney, glutamine synthetase is an important regulatory component of the availability of the ammonium ions to be excreted for defending systemic acid-base balance. Furthermore, they show that, in rodents, the regulation of renal glutamine synthetase is species-specific.