Adenosine triphosphate citrate lyase mediates hypocitraturia in rats.

Melnick, Joel Z.; Srere, Paul A.; Elshourbagy, Nabil A.; Moe, Orson W.; Preisig, Patricia A.; Alpern, Robert J.

doi:10.1172/jci119051

Cited by 70 publications

(61 citation statements)

References 38 publications

(37 reference statements)

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“…In the proximal tubule, citrate is reabsorbed across the apical membrane by a Na-coupled electrogenic transporter that transports citrate and succinate and is encoded by NaDC-1 (13,14,16,18,20,21). After transport into the cell, citrate is metabolized in the tricarboxylic acid cycle and by cytoplasmic ATP citrate lyase (10,11,22).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic metabolic acidosis is associated with nephrolithiasis and nephrocalcinosis, in part because of hypocitraturia (2,11,22). In rats, metabolic acidosis has been shown to increase proximal tubule citrate absorption, apical membrane Na ϩ -citrate 2Ϫ cotransporter activity, and cortical NaDC-1 mRNA and proximal tubule apical membrane protein abundances (2,5,7).…”

Section: Discussionmentioning

confidence: 99%

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OKP cells express the Na-dicarboxylate cotransporter NaDC-1

Aruga¹,

Pajor²,

Nakamura³

et al. 2004

American Journal of Physiology-Cell Physiology

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Urinary citrate concentration, a major factor in the formation of kidney stones, is primarily determined by its rate of reabsorption in the proximal tubule. Citrate reabsorption is mediated by the Na-dicarboxylate cotransporter-1 (NaDC-1). The opossum kidney (OKP) cell line possesses many characteristics of the renal proximal tubule. The OKP NaDC-1 (oNaDC-1) cDNA was cloned and encodes a 2.4-kb mRNA. When injected into Xenopus oocytes, the cotransporter is expressed and demonstrates Na-coupled citrate transport with a stoichiometry of Ն3 Na:1 citrate, specificity for di-and tricarboxylates, pH-dependent citrate transport, and pH-independent succinate transport, all characteristics of the other NaDC-1 orthologs. Chronic metabolic acidosis increases proximal tubule citrate reabsorption, leading to profound hypocitraturia and an increased risk for stone formation. Under the conditions studied, endogenous OKP NaDC-1 mRNA abundance is not regulated by changes in media pH. In OKP cells transfected with a green fluorescent protein-oNaDC-1 construct, however, media acidification increases Na-dependent citrate uptake, demonstrating posttranscriptional acid regulation of NaDC-1 activity.citrate; acid base; nephrocalcinosis; nephrolithiasis; opossum kidney cells INGESTED CITRATE IS ABSORBED in the intestine. When citrate is metabolized to neutral end products, base equivalents are produced. Citrate is present in the circulation at low concentrations and is freely filtered by the renal glomerulus. Its concentration in urine is important because it plays a key role in preventing nephrocalcinosis and nephrolithiasis. Citrate's urinary excretion rate is regulated primarily by its rate of reabsorption in the proximal tubule, a process mediated by an apical membrane electrogenic 3Na ϩ -citrate 2Ϫ cotransporter (16). Substantial evidence supports the idea that this apical membrane 3Na ϩ -citrate 2Ϫ cotransporter is encoded by the Nadicarboxylate cotransporter-1 (NaDC-1) (14). NaDC-1 expressed in Xenopus oocytes exhibits many characteristics of the apical membrane 3Na ϩ -citrate 2Ϫ transporter, including Nacoupled electrogenic transport, specificity for di-and tricarboxylates, pH-dependent citrate transport, and pH-independent succinate transport (14). NaDC-1 protein has been localized to the apical membrane of the proximal tubule (2). Chronic metabolic acidosis, which is known to increase proximal tubule citrate absorption as well as the activity of the apical membrane 3Na ϩ -citrate 2Ϫ cotransporter, also increases renal cortical NaDC-1 mRNA and apical membrane protein abundance (2, 5, 7). OKP cells are an opossum kidney cell line that possesses many characteristics of the renal proximal tubule. These cells have proved extremely useful in studying the mechanisms of regulation of proximal tubule H ϩ , Na ϩ , and phosphate transport. Recently, OK cells, another opossum kidney cell line, were demonstrated to exhibit Na-dependent citrate transport with many of the characteristics of NaDC-1 (6). The purpose of our study was to clone ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

OKP cells express the Na-dicarboxylate cotransporter NaDC-1

Aruga¹,

Pajor²,

Nakamura³

et al. 2004

American Journal of Physiology-Cell Physiology

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“…In metabolic alkalosis, proximal tubular citrate reabsorption is decreased, whereas it is increased in metabolic acidosis and chronic K ϩ depletion, the conditions associated with intracellular acidosis in the proximal tubular cells. Reduction of intracellular pH results in decreased citrate levels in the cytoplasm by increasing citrate entry into the mitochondria via proton-coupled tricarboxylate transport, followed by oxidative phosphorylation (6), and possibly by increasing cytosolic citrate utilization through ATP citrate lyase (47). This change stimulates citrate uptake into the cells, and citrate clearance decreases.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Rat Na+-Dicarboxylate Cotransporter

Chen

Shayakul

Berger

et al. 1998

Journal of Biological Chemistry

106

128

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The metabolism of Krebs cycle intermediates is of fundamental importance for eukaryotic cells. In the kidney, these intermediates are transported actively into epithelial cells. Because citrate is a potent inhibitor for calcium stone formation, excessive uptake results in nephrolithiasis due to hypocitraturia. We report the cloning and characterization of a rat kidney dicarboxylate transporter (SDCT1). In situ hybridization revealed that SDCT1 mRNA is localized in S3 segments of kidney proximal tubules and in enterocytes lining the intestinal villi. Signals were also detected in lung bronchioli, the epididymis, and liver. When expressed in Xenopus oocytes, SDCT1 mediated electrogenic, sodium-dependent transport of most Krebs cycle intermediates (K m ‫؍‬ 20-60 M), including citrate, succinate, ␣-ketoglutarate, and oxaloacetate. Of note, the acidic amino acids L-and D-glutamate and aspartate were also transported, although with lower affinity (K m ‫؍‬ 2-18 mM). Transport of citrate was pH-sensitive. At pH 7.5, the K m for citrate was high (0.64 mM), whereas at pH 5.5, the K m was low (57 M). This is consistent with the concept that the ؊2 form of citrate is the transported species. In addition, maximal currents at pH 5.5 were 70% higher than those at pH 7.5, and our data show that the ؊3 form acts as a competitive inhibitor. Simultaneous measurements of substrate-evoked currents and tracer uptakes under voltage-clamp condition, as well as a thermodynamic approach, gave a Na ؉ to citrate or a Na ؉ to succinate stoichiometry of 3 to 1. SDCT1-mediated currents were inhibited by phloretin. This plant glycoside also inhibited the SDCT1-specific sodium leak in the absence of substrate, indicating that at least one Na ؉ binds to the transporter before the substrate. The data presented provide new insights into the biophysical characteristics and physiological implications of a cloned dicarboxylate transporter.In kidney proximal tubules, reabsorption of Krebs cycle intermediates such as citrate, succinate, ␣-ketoglutarate, malate, and fumarate has been shown to be accomplished by Na ϩ -coupled transporters (1-9). Numerous studies have been performed in intact proximal tubules (10), isolated brush border membrane vesicles (BBMV) 1 (1-5, 11, 12), and basolateral membrane vesicles (BLMV) (12-14), mostly using citrate or succinate as substrates. In BBMV, succinate uptake was found to be mediated with low affinity (K m ϭ ϳ1 mM) (5,8,12,15). Studies on the pH dependence suggested that citrate is transported in its protonated divalent form (Cit Ϫ2 ) (1, 2, 12), whereas succinate is transported either in its deprotonated (Ϫ2) or protonated (Ϫ1) form (11). In addition, it was shown that the Ϫ3 form of citrate (trivalent form, Cit Ϫ3 ) inhibits transport of Cit Ϫ2 (11). Radiotracer studies revealed that the cotransport process exhibits a stoichiometry of 2-3 sodium ions/dicarboxylate molecule (2,8,16). On the other hand, experiments with a voltage-sensitive dye showed that the cotransport was electrogenic (14, 17), which favors a 3...

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“…Citraturia is a sensitive index of renal acidosis since the activity of the Na + /citrate cotransport is induced by acidosis, in parallel to the activity of citrate-metabolizing enzymes especially citrate lyase, aconitase and phosphoenolpyruvate carboxykinase whereas alkalinizing agents (and to a certain extent K itself) downregulate these systems [22,23] . 2-KG excretion seems to be submitted to regulation very similar to that for citrate [24] .…”

Section: Discussionmentioning

confidence: 99%

Excess Casein in the Diet Is Not the Unique Cause of Low-Grade Metabolic Acidosis: Role of a Deficit in Potassium Citrate in a Rat Model

Sabboh¹,

Besson²,

Tressol³

et al. 2006

Ann Nutr Metab

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This study examined the effects of a dietary model of protein excess and K anion salt deficit on the occurrence of metabolic acidosis in rat. Rats were adapted to diets containing either 13 or 26% casein, together with mineral imbalance, through lowering K/increasing sodium/omitting alkalinizing anions. For each protein level, a group of rats was supplemented with K citrate. Dietary K citrate resulted in neutral urinary pH, whatever the protein level. Urea excretion was higher in rats adapted to 26% casein than 13% casein diets, but K citrate enhanced this excretion and suppressed ammonium elimination. No citraturia could be observed in acidotic rats, whereas K citrate greatly stimulated citraturia and 2-ketoglutarate excretion. In conclusion, low-grade metabolic acidosis can occur with a moderate protein level in the diet. K citrate was apparently less effective in rats adapted to the 26% casein level than in those adapted to the 13% casein level with regard to magnesium, citrate and 2-ketoglutarate concentrations in urine.

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Adenosine triphosphate citrate lyase mediates hypocitraturia in rats.

Cited by 70 publications

References 38 publications

OKP cells express the Na-dicarboxylate cotransporter NaDC-1

OKP cells express the Na-dicarboxylate cotransporter NaDC-1

Characterization of a Rat Na+-Dicarboxylate Cotransporter

Excess Casein in the Diet Is Not the Unique Cause of Low-Grade Metabolic Acidosis: Role of a Deficit in Potassium Citrate in a Rat Model

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