The ability of the kidneys to generate base in defense of acid challenges is dependent upon the supply of glutamine. Glutamine availability in turn reflects either increased production or decreased utilization or both at some extrarenal sites. Recent evidence points to skeletal muscle and liver as the major sources of glutamine during metabolic acidosis. However the factor(s) involved in mobilizing this glutamine have not been elucidated. This proposal focuses upon glucocorticoids in the mobilization process as well as in the targeting of this nitrogen for ammoniagenesis (renal) or ureagenesis (hepatic). To accomplish this, net fluxes of glutamine are determined across sites of [1] mobilization - skeletal muscle, and [2] utilization - gut and kidney, to assess whether glucocorticocorticoids act at [1]. The regulatory [3] role of the liver in the incorporation of mobilized nitrogen into either glutamine or urea will be monitored by directly measuring glutamine fluxes and urea production across this organ. Glutamine fluxes and urea production are determined from arteriovenous glutamine concentration differences and from measured blood flows across [1] hindquarters [2[ portal drained viscera and kidneys and [3] liver. Flows at [1] are monitored by electromagnetic flow probe and at [2] and [3] by isotope dilution and Fick principle methods following 14C-PAH infusion. Quantitative comparisons between glutamine fluxes at [1] and [2] will be contrasted to the role of [3] in adrenalectomized rats, adx-acidotic rats and in both groups supplemented with glucocorticoids. This proposal should therefore determine if glucocorticoids mobilized muscle glutamine and, if so, whether they are essential in metabolic acidosis. Secondly, it will provide insight into whether glucocorticoids play a role in directing mobilized glutamine to renal or hepatic nitrogen deposition. Thirdly it should provide information about the mechanism governing the incorporation of mobilized nitrogen into hepatic ureagenesis. Understanding the mechanism by which muscle glutamine mobilization is coupled to renal ammoniagenesis rather than hepatic ureagenesis would prove helpful in treating the nitrogen wasting of numerous disease states.
| Meltzer, S J; Zhou, D; Weinstein, W M (1989) Tissue-specific expression of c-Ha-ras in premalignant gastrointestinal mucosae. Exp Mol Pathol 51:264-74 |
| Welbourne, T C (1988) Role of glucocorticoids in regulating interorgan glutamine flow during chronic metabolic acidosis. Metabolism 37:520-5 |
