Systemic succinate homeostasis and local succinate signaling affect blood pressure and modify risks for calcium oxalate lithogenesis

Ahlam Khamaysi, Shireen Anbtawee-Jomaa, Moran Fremder, Hadar Eini-Rider, Liana Shimshilashvili, Sara Aharon, Elina Aizenshtein, Tomer Shlomi, Audrey Noguchi, Danielle Springer, Orson W Moe, Nikolay Shcheynikov, Shmuel Muallem, Ehud Ohana

Research output: Contribution to journalArticle

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Abstract

Background In the kidney, low urinary citrate increases the risk for developing kidney stones, and elevation of luminal succinate in the juxtaglomerular apparatus increases renin secretion, causing hypertension. Although the association between stone formation and hypertension is well established, the molecular mechanism linking these pathophysiologies has been elusive. Methods To investigate the relationship between succinate and citrate/oxalate levels, we assessed blood and urine levels of metabolites, renal protein expression, and BP (using 24-hour telemetric monitoring) in male mice lacking slc26a6 (a transporter that inhibits the succinate transporter NaDC-1 to control citrate absorption from the urinary lumen). We also explored the mechanism underlying this metabolic association, using coimmunoprecipitation, electrophysiologic measurements, and flux assays to study protein interaction and transport activity. Results Compared with controlmice, slc26a6 -/- mice (previously shown to have low urinary citrate and to develop calcium oxalate stones) had a 40% decrease in urinary excretion of succinate, a 35% increase in serum succinate, and elevated plasma renin. Slc26a6 -/- mice also showed activity-dependent hypertension that was unaffected by dietary salt intake. Structural modeling, confirmed by mutational analysis, identified slc26a6 and NaDC-1 residues that interact and mediate slc26a6's inhibition of NaDC-1. This interaction is regulated by the scaffolding protein IRBIT, which is released by stimulation of the succinate receptor SUCNR1 and interacts with the NaDC-1/slc26a6 complex to inhibit succinate transport by NaDC-1. Conclusions These findings reveal a succinate/citrate homeostatic pathway regulated by IRBIT that affects BP and biochemical risk of calcium oxalate stone formation, thus providing a potential molecular link between hypertension and lithogenesis.

Original languageEnglish (US)
Pages (from-to)381-392
Number of pages12
JournalJournal of the American Society of Nephrology
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2019

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Calcium Oxalate
Succinic Acid
Homeostasis
Blood Pressure
Citric Acid
Hypertension
Renin
Juxtaglomerular Apparatus
Kidney
Kidney Calculi
Oxalates
Protein Transport
Proteins
Salts
Urine
Serum

ASJC Scopus subject areas

  • Nephrology

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Systemic succinate homeostasis and local succinate signaling affect blood pressure and modify risks for calcium oxalate lithogenesis. / Khamaysi, Ahlam; Anbtawee-Jomaa, Shireen; Fremder, Moran; Eini-Rider, Hadar; Shimshilashvili, Liana; Aharon, Sara; Aizenshtein, Elina; Shlomi, Tomer; Noguchi, Audrey; Springer, Danielle; Moe, Orson W; Shcheynikov, Nikolay; Muallem, Shmuel; Ohana, Ehud.

In: Journal of the American Society of Nephrology, Vol. 30, No. 3, 01.03.2019, p. 381-392.

Research output: Contribution to journalArticle

Khamaysi, A, Anbtawee-Jomaa, S, Fremder, M, Eini-Rider, H, Shimshilashvili, L, Aharon, S, Aizenshtein, E, Shlomi, T, Noguchi, A, Springer, D, Moe, OW, Shcheynikov, N, Muallem, S & Ohana, E 2019, 'Systemic succinate homeostasis and local succinate signaling affect blood pressure and modify risks for calcium oxalate lithogenesis', Journal of the American Society of Nephrology, vol. 30, no. 3, pp. 381-392. https://doi.org/10.1681/ASN.2018030277
Khamaysi, Ahlam ; Anbtawee-Jomaa, Shireen ; Fremder, Moran ; Eini-Rider, Hadar ; Shimshilashvili, Liana ; Aharon, Sara ; Aizenshtein, Elina ; Shlomi, Tomer ; Noguchi, Audrey ; Springer, Danielle ; Moe, Orson W ; Shcheynikov, Nikolay ; Muallem, Shmuel ; Ohana, Ehud. / Systemic succinate homeostasis and local succinate signaling affect blood pressure and modify risks for calcium oxalate lithogenesis. In: Journal of the American Society of Nephrology. 2019 ; Vol. 30, No. 3. pp. 381-392.
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abstract = "Background In the kidney, low urinary citrate increases the risk for developing kidney stones, and elevation of luminal succinate in the juxtaglomerular apparatus increases renin secretion, causing hypertension. Although the association between stone formation and hypertension is well established, the molecular mechanism linking these pathophysiologies has been elusive. Methods To investigate the relationship between succinate and citrate/oxalate levels, we assessed blood and urine levels of metabolites, renal protein expression, and BP (using 24-hour telemetric monitoring) in male mice lacking slc26a6 (a transporter that inhibits the succinate transporter NaDC-1 to control citrate absorption from the urinary lumen). We also explored the mechanism underlying this metabolic association, using coimmunoprecipitation, electrophysiologic measurements, and flux assays to study protein interaction and transport activity. Results Compared with controlmice, slc26a6 -/- mice (previously shown to have low urinary citrate and to develop calcium oxalate stones) had a 40{\%} decrease in urinary excretion of succinate, a 35{\%} increase in serum succinate, and elevated plasma renin. Slc26a6 -/- mice also showed activity-dependent hypertension that was unaffected by dietary salt intake. Structural modeling, confirmed by mutational analysis, identified slc26a6 and NaDC-1 residues that interact and mediate slc26a6's inhibition of NaDC-1. This interaction is regulated by the scaffolding protein IRBIT, which is released by stimulation of the succinate receptor SUCNR1 and interacts with the NaDC-1/slc26a6 complex to inhibit succinate transport by NaDC-1. Conclusions These findings reveal a succinate/citrate homeostatic pathway regulated by IRBIT that affects BP and biochemical risk of calcium oxalate stone formation, thus providing a potential molecular link between hypertension and lithogenesis.",
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T1 - Systemic succinate homeostasis and local succinate signaling affect blood pressure and modify risks for calcium oxalate lithogenesis

AU - Khamaysi, Ahlam

AU - Anbtawee-Jomaa, Shireen

AU - Fremder, Moran

AU - Eini-Rider, Hadar

AU - Shimshilashvili, Liana

AU - Aharon, Sara

AU - Aizenshtein, Elina

AU - Shlomi, Tomer

AU - Noguchi, Audrey

AU - Springer, Danielle

AU - Moe, Orson W

AU - Shcheynikov, Nikolay

AU - Muallem, Shmuel

AU - Ohana, Ehud

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background In the kidney, low urinary citrate increases the risk for developing kidney stones, and elevation of luminal succinate in the juxtaglomerular apparatus increases renin secretion, causing hypertension. Although the association between stone formation and hypertension is well established, the molecular mechanism linking these pathophysiologies has been elusive. Methods To investigate the relationship between succinate and citrate/oxalate levels, we assessed blood and urine levels of metabolites, renal protein expression, and BP (using 24-hour telemetric monitoring) in male mice lacking slc26a6 (a transporter that inhibits the succinate transporter NaDC-1 to control citrate absorption from the urinary lumen). We also explored the mechanism underlying this metabolic association, using coimmunoprecipitation, electrophysiologic measurements, and flux assays to study protein interaction and transport activity. Results Compared with controlmice, slc26a6 -/- mice (previously shown to have low urinary citrate and to develop calcium oxalate stones) had a 40% decrease in urinary excretion of succinate, a 35% increase in serum succinate, and elevated plasma renin. Slc26a6 -/- mice also showed activity-dependent hypertension that was unaffected by dietary salt intake. Structural modeling, confirmed by mutational analysis, identified slc26a6 and NaDC-1 residues that interact and mediate slc26a6's inhibition of NaDC-1. This interaction is regulated by the scaffolding protein IRBIT, which is released by stimulation of the succinate receptor SUCNR1 and interacts with the NaDC-1/slc26a6 complex to inhibit succinate transport by NaDC-1. Conclusions These findings reveal a succinate/citrate homeostatic pathway regulated by IRBIT that affects BP and biochemical risk of calcium oxalate stone formation, thus providing a potential molecular link between hypertension and lithogenesis.

AB - Background In the kidney, low urinary citrate increases the risk for developing kidney stones, and elevation of luminal succinate in the juxtaglomerular apparatus increases renin secretion, causing hypertension. Although the association between stone formation and hypertension is well established, the molecular mechanism linking these pathophysiologies has been elusive. Methods To investigate the relationship between succinate and citrate/oxalate levels, we assessed blood and urine levels of metabolites, renal protein expression, and BP (using 24-hour telemetric monitoring) in male mice lacking slc26a6 (a transporter that inhibits the succinate transporter NaDC-1 to control citrate absorption from the urinary lumen). We also explored the mechanism underlying this metabolic association, using coimmunoprecipitation, electrophysiologic measurements, and flux assays to study protein interaction and transport activity. Results Compared with controlmice, slc26a6 -/- mice (previously shown to have low urinary citrate and to develop calcium oxalate stones) had a 40% decrease in urinary excretion of succinate, a 35% increase in serum succinate, and elevated plasma renin. Slc26a6 -/- mice also showed activity-dependent hypertension that was unaffected by dietary salt intake. Structural modeling, confirmed by mutational analysis, identified slc26a6 and NaDC-1 residues that interact and mediate slc26a6's inhibition of NaDC-1. This interaction is regulated by the scaffolding protein IRBIT, which is released by stimulation of the succinate receptor SUCNR1 and interacts with the NaDC-1/slc26a6 complex to inhibit succinate transport by NaDC-1. Conclusions These findings reveal a succinate/citrate homeostatic pathway regulated by IRBIT that affects BP and biochemical risk of calcium oxalate stone formation, thus providing a potential molecular link between hypertension and lithogenesis.

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