The 1986 Borden Award Lecture. The role of the kidney in amino acid metabolism and nutrition

Abstract

Measurement of the arteriovenous differences for free amino acids across rat kidney reveals that glycine and citrulline are removed and serine and arginine are added to the circulation. In addition, glutamine is taken up in large quantities by kidneys of animals that need to excrete large quantities of acid (e.g., diabetic animals, NH4Cl-fed animals, and animals fed a high protein diet). Glutamine is the major precursor of urinary ammonia and thus renal glutamine metabolism plays a key role in acid-base homeostasis. This process occurs primarily in the cells of the convoluted proximal tubule. Glutamine carbon is converted to glucose in acidotic rats and is totally oxidized in dogs. Regulation of glutamine metabolism occurs at two levels: acute regulation and chronic regulation. Acute regulation is, in part, mediated through a fall in intracellular [H+]. This activates alpha-ketoglutarate dehydrogenase and, ultimately, glutaminase. Chronic regulation involves induction of key enzymes, including, in the rat, glutaminase, glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase. During the acidosis of prolonged starvation, the kidneys' requirement for glutamine must be met from muscle proteolysis and thus becomes a drain on lean body mass. Serine synthesis occurs by two separate pathways: from glycine by the combined actions of the glycine cleavage enzyme and serine hydroxymethyltransferase and from gluconeogenic precursors using the phosphorylated-intermediate pathway. Both pathways are located in the cells of the proximal tubule. Conversion of glycine to serine is ammoniagenic and the activity of the glycine cleavage enzyme is increased in acidosis. The function of serine synthesis by the phosphorylated-intermediate pathway is not apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Human splanchnic amino-acid metabolism

“…Interestingly, renal citrulline uptake was considerably higher than the rate at which citrulline was released from the splanchnic area, supporting that also other processes than glutamine metabolism provide citrulline for renal arginine synthesis (Castillo et al 1996). In line with earlier findings in humans (Brosnan 1987; Tizianello et al 1980, 1985), our data show a net renal release of serine into the systemic circulation. In contrast to our data, those studies also showed a significant renal uptake of glycine, which was interpreted as evidence for conversion of glycine to serine in the kidneys.…”

“…In contrast to our data, those studies also showed a significant renal uptake of glycine, which was interpreted as evidence for conversion of glycine to serine in the kidneys. A possible explanation for this discrepancy is that glycine is probably also supplied to the kidneys from sources other than direct uptake from the bloodstream (Brosnan 1987; Dejong et al 1998; Pitts and MacLeod 1972) This, in turn, offers an additional explanation why glycine uptake accounts for only 30 % of the net renal release of serine (van de Poll et al 2004). On average, 1.5 g glycine is taken up by the human kidneys per day (Tizianello et al 1980), followed by a release of 4 g serine per day (Tizianello et al 1985).…”

Glutamine Is Essential for Nitric Oxide Synthesis by Murine Macrophages

“…Enzymes present in the intestinal epithelium convert glutamine to glutamate and then via ornithine to citrulline [23]. The kidney then metabolizes gut citrulline to arginine [35]. We cannot explain the lack of NO synthesis by stimulated macrophages incubated in culture medium devoid of both arginine and glutamine but supplemented with citrulline by the lack of renal tissue in our cell cultures, since RAW 264.7 macrophages have been shown to convert citrulline to arginine in vitro [36].…”

A Computational Approach to Estimate Interorgan Metabolic Transport in a Mammal

“…In contrast, enzymes involved in serine glycine conversion, glycine degradation by glycine cleavage enzyme, and glutathione synthesis from glycine were exclusively expressed in liver and kidney. Therefore, we predict that serine may be involved in an inter-organ transport in which adipose synthesizes and releases serine as the precursor of glycine for liver and kidney [32], [35], [36] (Figure S6C). Evidently, this novel pathway is still hypothetical and needs to be experimentally validated using isotope labeled compounds.…”