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J Am Soc Nephrol. 2019 Feb 6. pii: ASN.2018030277. doi: 10.1681/ASN.2018030277. [Epub ahead of print]

Systemic Succinate Homeostasis and Local Succinate Signaling Affect Blood Pressure and Modify Risks for Calcium Oxalate Lithogenesis.

Author information

1
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
2
Department of Computer Science and.
3
Department of Biology, Technion, Haifa, Israel.
4
Murine Phenotyping Core, National Heart, Lung and Blood Institute, Bethesda, Maryland.
5
Department of Internal Medicine.
6
Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, and.
7
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas; and.
8
Epithelial Signaling and Transport Section, National Institute of Dental Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
9
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; ohanaeh@bgu.ac.il.

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 control mice, 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.

KEYWORDS:

SUCNR1; calcium-oxalate kidney stones; citrate; ion transport; signaling; succinate

PMID:
30728179
DOI:
10.1681/ASN.2018030277

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