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

Solbu, Tom Tallak; Boulland, Jean-Luc; Zahid, Wasim; Bredahl, May Kristin Lyamouri; Amiry-Moghaddam, Mahmood; Storm‐Mathisen, Jon; Roberg, Bjørg; Chaudhry, Farrukh A.

doi:10.1681/asn.2004060433

Cited by 62 publications

(75 citation statements)

References 49 publications

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“…Several members of the SLC38 family have been studied extensively in heterologous and other in vitro systems [18,20,23,34] but their function in vivo is mainly unknown. Here we report a severe phenotype of mice lacking Snat3 due to an early stop codon introduced by random ENUmutagenesis.…”

Section: Discussionmentioning

confidence: 99%

“…SNAT3 is highly abundant in liver, kidney, and brain, and expression has also been reported for adipose tissue, pancreas, skeletal muscle, and eye. In kidney, SNAT3 is mainly localized to the proximal tubule, in liver to both perivenous and periportal hepatocytes, and in brain mostly in astrocytes and endothelial cells of the blood-brain-barrier [17][18][19][20][21]. In the brain, SNAT3 and SNAT5…”

Section: Introductionmentioning

confidence: 99%

“…In the liver, SNAT3 is likely to be a candidate for both periportal uptake and perivenous efflux of glutamine, which is essential for the detoxification of ammonia delivered via the portal blood and excreted as urea [6,21]. Furthermore, SNAT3 mRNA and protein expression in the kidney is increased in response to metabolic acidosis possibly providing glutamine for ammoniagenesis in the proximal tubule cell [18,20,[23][24]. Plasma glutamine levels decrease substantially during metabolic acidosis [25] and glutamine flow is redirected from the splanchnic bed to the kidney with SNAT3 proposed to deliver glutamine for renal ammoniagenesis.…”

Section: Introductionmentioning

confidence: 99%

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Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan

Busque

Sailer

et al. 2015

Pflugers Arch - Eur J Physiol

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Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney. ABSTRACTGlutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, loss of the Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3 deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and GABA levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan

Busque

Sailer

et al. 2015

Pflugers Arch - Eur J Physiol

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“…The proximal tubule is the major expression site of glutaminase, a key enzyme that generates Glu+NH 4 + from Gln. 49 Because the proximal tubules were severely damaged, the rats in group Lys might have been unable to convert Gln to Glu+NH 4 + , even under the high Gln condition. The rats fed the LP diet containing L-Lys without adenine showed an elevation in Glu, which is in sharp contrast with the rats with adenine.…”

Section: Discussionmentioning

confidence: 99%

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Shimomura¹,

Matsui²,

Hamano

et al. 2014

Journal of the American Society of Nephrology

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Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary L-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+L-lysinezHCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. L-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary L-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of L-lysine. Dietary L-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/ phosphate solution. In conclusion, dietary supplementation of L-lysine ameliorated VC by modifying key pathways that exacerbate VC.

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“…Renal ammoniagenesis occurs primarily in the proximal tubule and glutamine is the primary substrate (48). In the proximal tubule, glutamine uptake occurs through the combination of the apical Na 1 -dependent neutral amino acid transporter-1, and the basolateral sodiumcoupled neutral amino acid transporter-3 (SNAT3) (49). Changes in ammoniagenesis, such as during metabolic acidosis, are associated with changes in the expression of SNAT3, but not expression of apical Na 1 -dependent neutral amino acid transporter-1 (50).…”

Section: Renal Ammonia Handlingmentioning

confidence: 99%

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

Weiner

Mitch

Sands

2015

Clinical Journal of the American Society of Nephrology

352

265

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Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acidbase homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance.

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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

Cited by 62 publications

References 49 publications

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

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