Biochemical pathways and modulators of renal ammoniagenesis

The renal proximal tubule contains a variety of biochemical pathways, which can metabolize glutamine, the major substrate for renal ammoniagenesis. The intramitochondrially located phosphate-dependent glutaminase (PDG) pathway, rather than the various cytosolic pathways, appears to play the predominant role in regulating the rate of renal NH3 production. Acute acidosis stimulates NH3 production by activating alpha-ketoglutarate dehydrogenase and secondarily glutamate dehydrogenase; whereas the adaptation to chronic metabolic acidosis results primarily from enhanced glutamine transport into the mitochondria and possibly increased activity of PDG. There is no adaptation of ammoniagenesis to chronic respiratory acidosis, because the proximal tubular intracellular pH is not decreased. Alkalosis suppresses NH3 formation but the precise mechanism is not clarified. Ammoniagenesis can be modulated independent of acid-base status by a variety of factors including potassium homeostasis, TCA cycle intermediates, hormones which increase cAMP, prostaglandin F2 alpha, insulin, growth hormone, angiotensin II, corticosteroids, aldosterone, and tubular flow rate.