Activation of oxoglutarate dehydrogenase in the kidney in response to acute acidosis.
1. Activation by H+ and by Ca2+ of 2-oxoglutarate dehydrogenase extracted from mitochondria of normal or acidotic rat kidney is described. This effect, first shown for the enzyme from heart by McCormack & Denton [Biochem. J. (1979) 180, 533--544], is of a regulatory importance in kidney, in which organ, in contrast with heart, increased flux occurs during acute acidosis. 2. In renal-cortical tubules, 2-oxoglutarate concentration fell within 1 min of decreasing the pH and rose again 1--3 min after increasing the pH of the medium. The extent of the decrease in 2-oxoglutarate was directly related to the decrease in pH. A similar fall in the oxoglutarate concentration in the whole perfused kidney was noted within 5 min of inducing acidosis. 3. In tubules, the rates of gluconeogenesis and ammoniagenesis from 1 mM-glutamine were increased by 64 and 33% respectively on decreasing pH to 7.0, the increase in rates being proportional to the fall in pH between 7.4 and 7.0. 4. The increased rates of renal ammoniagenesis and gluconeogenesis seen in acute acidosis in vitro can be accounted for by the increased activity of 2-oxoglutarate dehydrogenase and the tissue concentrations of 2-oxoglutarate when calculated from the Km determined at normal and acidotic pH. 5. The decrease in 2-oxoglutarate concentration seen in acute acidosis implies a fall in intramitochondrial pH in kidney, and is the result of two phenomena, accelerated disposal via 2-oxoglutarate dehydrogenase and maintenance of near equilibrium of glutamate dehydrogenase.
D000141:Acidosis, Renal Tubular / Q000201:enzymology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D051381:Rats
D007656:Ketoglutaric Acids; D007658:Ketone Oxidoreductases; D007655:Ketoglutarate Dehydrogenase Complex; D002118:Calcium