ACID-BASE BALANCE REGULATION OF RENAL METABOLISM

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This project is an investigation into regulation of intermediary metabolism in the kidney by acid-base changes and the relationship to physicologic processes involved in acid-base homeostasis. The emphasis in the project is to relate properties of the inner mitochondrial membrane to two different metabolic responses by the kidney to alterations in acid-base balance. (1) During chronic metabolic acidosis renal ammoniagenesis from glutamine increases strikingly. Previous work has suggested that a major factor in this adaptive response is an increase in acidosis in glutamine transport by its carrier in the inner mitochondrial membrane, leading to delivery of more glutamine to phosphate dependent glutaminase. Further evidence for adaptation of the glutamine transporter will be sought in studies on mitochondria from dogs with chronic metabolic or respiratory acidosis. Changes in mitochondrial glutamine transport and metabolism will be correlated with NH4+excretion, NH3 synthesis and glutamine utilization in intact animals with chronic metabolic or respiratory acidosis. (2) Levels in renal cortex of a number of citric acid cycle and related substrates decrease in acute metabolic acidosis and increase in metabolic alkalosis. We postulate that these changes are the result of substrate shifts occurring in response to variations in the mitochondrial pH gradient. Studies will be carried out in isolated kidney tubules and in mitochondria to determine the validity of this hypothesis.