Pathways of glutamine and organic acid metabolism in renal cortex in chronic metabolic acidosis

Abstract

A B S T R A C T The metabolism of labeled glutamine and of several labeled organic acid anions was compared in tissue slices of renal cortex from chronically acidotic and alkalotic littermate dogs. 'NHa formation and 'N-amideglutamine utilization were significantly increased by slices from acidotic animals providing further evidence for the similarity of the metabolic responses seen in the tissue slice system and the physiologic effects produced by chronic metabolic acidosis on renal metabolism in the intact animal. Slices from acidotic dogs formed more "CO2 and glucose-"C than did slices from alkalotic animals when labeled glutamine, citrate, or malate was used as substrate but 'COa production from pyruvate-1-l4C was slightly reduced in acidotic tissue. With most of the substrates used glucose-"'C formation was small compared with 14CO2 formation. Using the amount of glucose-'4C formed, the expected 14CO2 production was calculated based on the hypothesis that the primary site of action of metabolic acidosis is on a cytoplasmic step in gluconeogenesis. The actual difference in 1'CO2 production between slices from acidotic and alkalotic animals always greatly exceeded this predicted amount, indicating that stimulation of gluconeogenesis represents a minor metabolic response to chronic metabolic acidosis. Evidence from experiments with citrate labeled in various positions showed that metabolic acidosis has its principal effect on an early step in substrate metabolism which must be intramitochondrial in location.

The Renal Excretion of Hydrogen Ions in Infants and Children

“…However, recent studies of P itts et al [9] in the intact functioning kidney of the dog demonstrate that renal gluconeogenesis in the dog is not rate-limiting for the production and excretion of ammonia in either acidosis or alkalosis. This was confirmed by Simpson [13] in his study in tissue slices of renal cortex from chronically acidotic dogs.…”

Effect of Inhibition of Gluconeogenesis on Ammonia Production in the Perfused Rat Kidney

“…This follows from the demonstration that glutamate dehydrogenase is maintained at equilibrium in a variety of metabolic states (Hems & Brosnan, 1971 Simpson (1972) on the basis of isotopic findings in renal mitochondria, may occur in perfused kidney. Nevertheless, the specific site of inhibition by 3-mercaptopicolinic acid on phosphoenolpyruvate wboxykinase makes it probable that this is the key enzyme determining the rate of glutamine consumption and of formation of ammonia.…”

Biochemical Aspects of Renal Ammonia Formation in Metabolic Acidosis

“…However, there is no doubt about the existence of this effect, which is brought out in low-Ca++ media [109,110] and which presumably involves mechanisms whereby cytoplasmic H+ controls renal gluconeogenesis (or at least intra cellular metabolic events) at some stage during acidosis. Isolated mito chondria can respond to acidification of the incubation medium by an in crease in glutamine oxidation to carbon dioxide [111], suggesting that part of the directly renal biochemical effects of acute acidosis may reside in mito chondria, perhaps in reactions of citrate [26] [35]. Changes such as the above occur in various cellular compartments, in a complex fashion.…”