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J. Biol. Chem., Vol. 278, Issue 40, 38159-38166, October 3, 2003

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Inhibition of Glutamine Synthetase in the Mouse Kidney

A NOVEL MECHANISM OF ADAPTATION TO METABOLIC ACIDOSIS^*

Agnès Conjard, Ola Komaty, Hélène Delage, Michelle Boghossian, Mireille Martin, Bernard Ferrier and Gabriel Baverel 

From the Laboratoire de Physiopathologie Métabolique et Rénale, INSERM Unité 499, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France

As part of a study on the regulation of renal ammoniagenesis 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.

Received for publication, March 20, 2003 , and in revised form, July 9, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Lab. de Physiopathologie Métabolique et Rénale, INSERM U499, Faculté deMédecine Laennec, rue G. Paradin, 69372 Lyon Cedex 08, France. Tel.: 33-478-778-665; Fax: 33-478-778-739; E-mail: baverel{at}laennec.univ-lyon1.fr.

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