Biochemical Aspects of Renal Ammonia Formation in Metabolic Acidosis

Abstract

In omnivorous creatures, the diet is acidogenic, especially as a result of the meat content, which gives rise to phosphoric and sulphuric acids, i.e., to metabolic acidosis. In the short term, metabolic acids are buffered by tissue proteins and bicarbonate (the ‘alkali reserve’). In the longer term, acid must be excreted, or neutralized with base which is also generated from the diet, by conversion of dietary amino-nitrogen to ammonia. The final steps of this process occur in the kidney, which converts circulating glutamine to ammonia, and to carbon products such as glucose and carbon dioxide, by metabolic reactions which adapt during acidosis to generate more ammonia and maintain an increased renal ammonia content. The complex mechanisms which govern the formation of ammonia, glucose and carbon dioxide from glutamine, involving the reactions of amino acids, the tricarboxylic acid cycle, and gluconeogenesis, are reviewed.

Effects of 2-Oxoglutarate Concentrations on Canine Slice Ammoniagenesis

“…many hypotheses concerning enhancement of ammoniagenesis during acidosis in dogs consider its concentration as a potential regulator of GDH [4][5][6],…”

“…The importance of other pathways for ammoniagenesis in dogs is uncertain [2][3][4], 2-Oxoglutarate occupies an important position in the production of ammonia. Since the GDH is potentially reversible, an accumulation of 2-oxoglutarate by canine kidneys could regulate glutamate ammonia genesis by end-product inhibition [5,6]. In turn, a buildup ofglutamate might then slow the deamidation of glutamine via inhibition of PDG [7,8], Accordingly, a decrease in the Rx renal concentration of 2-oxoglutarate could reverse the chain of events, and augment arnmoniagenesis through GDH and PDG [9], Another possibility exists whereby 2-oxoglutarate buildup controls renal am monia production.…”

“…Thus, lesser concentrations of 2-oxoglutarate could enhance ammoniagenesis via deinhibition of mitochondrial trans port of glutamine. By either mechanism, the concentration of 2-oxoglutarate is poten tially an important regulator of ammonia production, as pointed out in recent reviews on the subject [4,11], The renal concentra tion of 2-oxoglutarate has been considered as a potential regulator of renal ammoniagenesis in dogs [4][5][6], Infusions of2-oxoglutarate into dogs have been shown to decrease renal arnmoniagenesis [12.13]: however, the mechanism for the depression was not ascer tained.…”

The Reduction in Urinary Glutamate Excretion Is Responsible for Lowering Urinary pH in Pink Urine Syndrome

“…A reduction in UpH in PUS has been shown to be strongly correlated with oxidative stress (OS) markers in the urine (Ogawa et al 2015b). UpH is controlled by the secretion of urinary ammonia (NH 3 ) from the renal proximal tubules (RPTs), where it is converted into ammonium ions (NH 3 + H + → NH 4 + ) (Hems 1975;Zipp and Tannen 1983;RodriguezNichols et al 1984). The UpH decreases when the supply of H + is so high (acidosis) that it cannot be counteracted by this NH 3 , or when the secretion of NH 3 from the RPT decreases.…”

“…The UpH decreases when the supply of H + is so high (acidosis) that it cannot be counteracted by this NH 3 , or when the secretion of NH 3 from the RPT decreases. Synthesis of NH 3 in the RPTs involves two reactions: the production of glutamate from glutamine, and the production of α-ketoglutarate from glutamate (Hems 1975;Zipp and Tannen 1983;Rodriguez-Nichols et al 1984;Nissim 1999;Tapiero et al 2002;Karim et al 2005) (Fig. 1).…”