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Abstract: FR-PO328

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

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Ohana, Ehud, Ben Gurion university of the Negev, Beer Sheva, israel, Israel
  • Khamaysi, Ahlam, Ben Gurion university of the Negev, Beer Sheva, israel, Israel
  • Shimshilashvili, Liana, Ben Gurion university of the Negev, Beer Sheva, israel, Israel
Background

Succinate and citrate are important metabolic signaling molecules. In the kidney, low urinary citrate increases the risk for developing kidney stones, while an elevation of luminal succinate in the juxtaglomerular apparatus increases renin secretion and can cause hypertension. Although the association between kidney stone formation and hypertension is well established in humans, the molecular mechanisms that link these pathophysiologies remain elusive.

Methods

We have utilized electrophysiological measurements, fluorescent imaging and radiolabeled molecules to monitor transport rptoein activity in live cells. In addition we utilized biochemical assays to monitor protein expression and interaction. Finally, slc26a6-/- mice were utilized to test the physiological effects of impaired succinate and citrate homeostasis.

Results

Here, we reveal an intimate relationship between succinate and citrate/oxalate in vivo and study the molecular mechanism of this association. Deletion of the succinate/citrate transport inhibitor, the slc26a6 transporter, in male mice resulted in 40% decrease in urinary excretion of succinate, elevated plasma renin and activity-dependent hypertension. Structural modeling confirmed by mutational analysis identified the NaDC-1/slc26a6 interacting surfaces that mediate inhibition of the succinate/citrate transporter, NaDC-1, by slc26a6. This interaction is regulated by the scaffolding protein IRBIT, which interacts with the NaDC-1/slc26a6 complex and is released upon stimulation of the succinate receptor, SUCNR1 to inhibit succinate transport by NaDC-1.

Conclusion

These findings reveal a succinate/citrate homeostatic pathway regulated by IRBIT that controls blood pressure and biochemical risk of calcium-oxalate stone formation and provides a novel potential molecular link between these syndromes. This may have significant clinical implications for stone formation and the associated hypertension.