Localization of the calcium-regulated citrate transport process in proximal tubule cells

Hering-Smith, Kathleen S.; Mao, Weibo; Schiro, Faith; Coleman-Barnett, Joycelynn; Pajor, Ana M.; Hamm, L. Lee

doi:10.1007/s00240-014-0653-4

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…CaSR is activated only when [Ca 2+ ] o is in the range of 0.5 – 2 mM [Ca 2+ ] o 8 . Since the CaSR is at the apical membrane of the proximal tubule, CaSR activation may be the basis of the apical calcium-sensitive dicarboxylate transport we previously reported 15–17 . If CaSR regulates apical dicarboxylate transport due to changes in luminal [Ca 2+ ] o levels, then apical addition of CaSR agonists may be used to test this hypothesis.…”

Section: Resultsmentioning

confidence: 82%

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Calcium receptor signaling and citrate transport

et al. 2018

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The calcium sensing receptor (CaSR) in the distal nephron decreases the propensity for calcium stones. Here we investigate if the apical CaSR in the proximal tubule also prevents stone formation acting via regulation of apical dicarboxylate and citrate transport. Urinary citrate, partially reabsorbed as a dicarboxylate in the proximal tubule lumen, inhibits stone formation by complexing calcium. We previously demonstrated a novel apical calcium-sensitive dicarboxylate transport system in OK proximal tubule cells. This calcium-sensitive process has the potential to modulate the amount of citrate available to complex increased urinary calcium. Using isotope labeled succinate uptake in OK cells along with various pharmacologic tools we examined whether the CaSR alters apical dicarboxylate transport and through which signal transduction pathways this occurs. Our results indicate that in the proximal tubule CaSR adjusts apical dicarboxylate transport, and does so via a CaSR → G → PKC signaling pathway. Thus, the CaSR may decrease the propensity for stone formation via actions in both proximal and distal nephron segments.

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Section: Resultsmentioning

confidence: 82%

“…As previously described, OK cells were maintained in MEM containing 26 mM HCO 3 − supplemented with 10% FCS (Invitrogen), 25 mM HEPES, 11 mM L-glutamine and 100 IU/ml penicillin in a humidified atmosphere of 5% CO 2 at 37°C 15–17 . Cell monolayers were grown on 24-well plates (Corning-Costar), with media changes every 2 days.…”

Section: Methodsmentioning

confidence: 99%

Calcium receptor signaling and citrate transport

et al. 2018

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“…This alternative citrate transport mechanism is likely to be related to the recently described calcium‐regulated apical citrate transport activity (Hering‐Smith et al. , ), which is known to be stimulated by extracellular acidosis (Hering‐Smith et al. ).…”

Section: Discussionmentioning

confidence: 88%

Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling

et al. 2016

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The bicarbonate transporter, NBCe1 (SLC4A4), is necessary for at least two components of the proximal tubule contribution to acid‐base homeostasis, filtered bicarbonate reabsorption, and ammonia metabolism. This study's purpose was to determine NBCe1's role in a third component of acid‐base homeostasis, organic anion metabolism, by studying mice with NBCe1 deletion. Because NBCe1 deletion causes metabolic acidosis, we also examined acid‐loaded wild‐type adult mice to determine if the effects of NBCe1 deletion were specific to NBCe1 deletion or were a non‐specific effect of the associated metabolic acidosis. Both NBCe1 KO and acid‐loading decreased citrate excretion, but in contrast to metabolic acidosis alone, NBCe1 KO decreased expression of the apical citrate transporter, NaDC‐1. Thus, NBCe1 expression is necessary for normal NaDC‐1 expression, and NBCe1 deletion induces a novel citrate reabsorptive pathway. Second, NBCe1 KO increased 2‐oxoglutarate excretion. This could not be attributed to the metabolic acidosis as experimental acidosis decreased excretion. Increased 2‐oxoglutarate excretion could not be explained by changes in plasma 2‐oxoglutarate levels, the glutaminase I or the glutaminase II generation pathways, 2‐oxoglutarate metabolism, its putative apical 2‐oxoglutarate transporter, OAT10, or its basolateral transporter, NaDC‐3. In summary: (1) NBCe1 is necessary for normal proximal tubule NaDC‐1 expression; (2) NBCe1 deletion results in stimulation of a novel citrate reabsorptive pathway; and (3) NBCe1 is necessary for normal 2‐oxoglutarate metabolism through mechanisms independent of expression of known transport and metabolic pathways.

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“…Citrate is an important inhibitor of calcium-stone formation and most of the citrate reabsorption is thought to occur via a sodium dicarboxylate transporter (NaDC1) located in the apical membrane. NaDC1 has been localized in opossum kidney proximal tubule cells and was responsible for calcium regulated citrate reabsorption in proximal tubules [ 22 ]. In the rat model, increased NaDC1 expression on the renal proximal tubule epithelial cells was associated with a decline in urinary citrate excretion, suggesting this transporter could play an important role in nephrolithiasis development [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

A Drosophila genetic model of nephrolithiasis: transcriptional changes in response to diet induced stone formation

Chung

Turney

2017

BMC Urol

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BackgroundUrolithiasis is a significant healthcare issue but the pathophysiology of stone disease remains poorly understood. Drosophila Malpighian tubules were known to share similar physiological function to human renal tubules. We have used Drosophila as a genetic model to study the transcriptional response to stone formation secondary to dietary manipulation.MethodsWild-type male flies were raised on standard medium supplemented with lithogenic agents: control, sodium oxalate (NaOx) and ethylene glycol (EG). At 2 weeks, Malpighian tubules were dissected under polarized microscope to visualize crystals. The parallel group was dissected for RNA extraction and subsequent next-generation RNA sequencing.ResultsCrystal formation was visualized in 20%(±2.2) of flies on control diet, 73%(±3.6) on NaOx diet and 84%(±2.2) on EG diet. Differentially expressed genes were identified in flies fed with NaOx and EG diet comparing with the control group. Fifty-eight genes were differentially expressed (FDR <0.05, p < 0.05) in NaOx diet and 20 genes in EG diet. The molecular function of differentially expressed genes were assessed. Among these, Nervana 3, Eaat1 (Excitatory amino acid transporter 1), CG7912, CG5404, CG3036 worked as ion transmembrane transporters, which were possibly involved in stone pathogenesis.ConclusionsWe have shown that by dietary modification, stone formation can be manipulated and visualized in Drosophila Malpighian tubules. This genetic model could be potentially used to identify the candidate genes that influence stone risk hence providing more insight to the pathogenesis of human stone disease.

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Localization of the calcium-regulated citrate transport process in proximal tubule cells

Cited by 9 publications

References 26 publications

Calcium receptor signaling and citrate transport

Calcium receptor signaling and citrate transport

Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling

A Drosophila genetic model of nephrolithiasis: transcriptional changes in response to diet induced stone formation

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