The aim of this research program is to increase the understanding of the mechanisms involved in the modulation of renal glutamine metabolism during metabolic acidosis. Because of its clinical relevance diabetic ketoacidosis is the experimental model to be studied. Other forms of metabolic acidosis (NH4C1, HC1) will be examined for comparison. Indirect evidence strongly suggests that the increase in renal glutamine utilization in acidotic animals is part of a more generalized response in renal oxidative metabolism to acidosis. In order to obtain direct verification for this hypothesis, the effects of acidosis on the uptake of the major respiratory substrates (free fatty acids, lactate, glutamine, etc.) from the circulation by the kidneys will be determined in vivo. Renal oxygen consumption will be measured under the same conditions. Since the oxidative steps of glutamine metabolism take place in the mitochondria, it is important to examine the ability of renal mitochondria from acidotic animals to oxidize the intermediates (Alpha-ketoglutarate, succinate, ect.) of the glutamine metabolic pathway. Therefore, the question of whether mitochondria from the kidneys of acidotic rats have an increased capacity to oxidize pathway intermediates and what biochemical changes take place in the mitochondria to increase their oxidative capacity will be determined using isolated mitochondria. Possible mechanisms which could increase mitochondrial oxidation of respiratory substrates and that will be tested are 1) an increase in mitochondrial concentration of free calcium (Ca++), a known activator of several mitochondrial oxidative enzymes; 2) increase in the activity of the mitochondrial adenine nucleotide translocase system which is known to regulate the rate of oxidative phosphorylation; and 3) increase in the activity level of the mitochondrial electron transport chain.
| Goldstein, L (1989) Organic solute profiles and transport in the rat renal medulla. Am J Kidney Dis 14:310-2 |
| Chauncey, B; Leite, M V; Goldstein, L (1988) Renal sorbitol accumulation and associated enzyme activities in diabetes. Enzyme 39:231-4 |
| Goldstein, L (1987) Renal substrate utilization in normal and acidotic rats. Am J Physiol 253:F351-7 |
