Glutamine metabolism in the kidney during induction of, and recovery from, metabolic acidosis in the rat

Abstract

Experiments were carried out on rats to evaluate the possible regulatory roles of renal glutaminase activity, mitochondrial permeability to glutamine, phosphoenolpyruvate carboxykinase activity and systemic acid-base changes in the control of renal ammonia (NH(3) plus NH(4) (+)) production. Acidosis was induced by drinking NH(4)Cl solution ad libitum. A pronounced metabolic acidosis without respiratory compensation [pH=7.25; HCO(3) (-)=16.9mequiv./litre; pCO(2)=40.7mmHg (5.41kPa)] was evident for the first 2 days, but thereafter acid-base status returned towards normal. This improvement in acid-base status was accompanied by the attainment of maximal rates of ammonia excretion (onset phase) after about 2 days. A steady rate of ammonia excretion was then maintained (plateau phase) until the rats were supplied with tap water in place of the NH(4)Cl solution, whereupon pCO(2) and HCO(3) (-) became elevated [55.4mmHg (7.37kPa) and 35.5mequiv./litre] and renal ammonia excretion returned to control values within 1 day (recovery phase). Renal arteriovenous differences for glutamine always paralleled rates of ammonia excretion. Phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase activities and the rate of glutamine metabolism (NH(3) production and O(2) consumption) by isolated kidney mitochondria all increased during the onset phase. The increases in glutaminase and in mitochondrial metabolism continued into the plateau phase, whereas the increase in the carboxykinase reached a plateau at the same time as did ammonia excretion. During the recovery phase a rapid decrease in carboxykinase activity accompanied the decrease in ammonia excretion, whereas glutaminase and mitochondrial glutamine metabolism in vitro remained elevated. The metabolism of glutamine by kidney-cortex slices (ammonia, glutamate and glucose production) paralleled the metabolism of glutamine in vivo during recovery, i.e. it returned to control values. The results indicate that the adaptations in mitochondrial glutamine metabolism must be regulated by extra-mitochondrial factors, since glutamine metabolism in vivo and in slices returns to control values during recovery, whereas the mitochondrial metabolism of glutamine remains elevated.

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK

“…Regulation of hepatic and pancreatic GLUT2 expression by glucose depends on glucose metabolism (17,42), whereas that of renal glutaminase and glutamate dehydrogenase depends on glutamine metabolism (12,39). Thus, in several tissues and for several enzyme systems, upregulation requires metabolism of their substrates.…”

The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression

“…Insulin's ability to reduce glucose production is preserved in cultured hepatocytes, but not in cultured kidney epithelial cells, the site of renal glucose production. The latter display hormonal (19,20) and pH-regulated gluconeogenesis (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), but have never been shown to be sensitive to insulin inhibition.…”

Induction and Targeting of the Glutamine Transporter SN1 to the Basolateral Membranes of Cortical Kidney Tubule Cells during Chronic Metabolic Acidosis Suggest a Role in pH Regulation

“…Glutamine is mobilized from skeletal muscle, the major site for glutamine storage, as well as intestinal cells (1). Simultaneously, glutamine metabolism increases in the kidney during acidosis (2). Increased expression levels and activities of the mitochondrial enzymes phosphate-activated glutaminase (PAG) and glutamate dehydrogenase (GDH) occur during chronic metabolic acidosis (CMA), resulting in degradation of glutamine to 2-oxoglutarate and formation of two ions of NH 4 ϩ (3).…”