Kidney stone formation is associated with hypertension but the underlying mechanism is unclear. Now, Ehud Ohana and colleagues report that a succinate homeostatic pathway provides a potential link between calcium oxalate (CaOx) lithogenesis and increased blood pressure.

“We previously identified a metabolic pathway that regulates citrate and oxalate transport via the citrate and succinate transporter NaDC1 and the oxalate transporter SLC26A6,” says Ohana. “These transporters form a complex and SLC26A6 inhibits NaDC1 activity. As this mechanism also governs transepithelial succinate transport, we hypothesized that SLC26A6–/– mice, which develop CaOx stones, hyperoxaluria and hypocitraturia, would also have impaired succinate homeostasis.”

The researchers found that in addition to elevated serum succinate levels, SLC26A6–/– mice have increased plasma renin levels and show activity-dependent hypertension. These findings were consistent with a previous report that succinate might contribute to blood pressure regulation by inducing renin release in the juxtaglomerular apparatus. The researchers show that luminal succinate sensing via the succinate receptor SUCNR1 regulates and orchestrates transepithelial succinate transport by inducing the translocation of a scaffolding protein, IRBIT, which interacts with the NaDC1–SLC26A6 complex and inhibits succinate transport by NaDC1.

“Our findings suggest that the molecular mechanism of succinate–citrate–oxalate homeostasis that we have delineated protects against kidney stone formation and controls blood pressure,” concludes Ohana. “Succinate and citrate signalling and transport mechanisms should be considered potential therapeutic targets for the treatment of hypertension and urolithiasis.”