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

作者：Ahlam Khamaysi, Shireen Anbtawee-Jomaa, Moran Fremder, Hadar Eini-Rider, Liana Shimshilashvili, Sara Aharon, É. M. Aizenshtein, Tomer Shlomi, Audrey Noguchi, Danielle Springer, Orson W. Moe, Nikolay Shcheynikov, Shmuel Muallem, Ehud Ohana · 发表于：Journal of the American Society of Nephrology · 年份：2019 · DOI：10.1681/asn.2018030277 · 被引用次数：48 · 研究领域：Kidney Stones and Urolithiasis Treatments、Parathyroid Disorders and Treatments、Chronic Kidney Disease and Diabetes

Significance Statement The association between kidney stone formation and hypertension is well established, but the molecular mechanism linking the two diseases has been unclear. In this study, the authors describe a metabolic pathway that tightly modulates homeostasis of the metabolite succinate. In this pathway, succinate uptake regulates BP, possibly through regulation of the renin-angiotensin system. The same pathway also regulates urinary citrate and oxalate, thus protecting against calcium oxalate stone formation. Mice lacking the slc26a6 transporter, a major succinate transport inhibitor, exhibit reduced urinary levels of succinate and citrate, increased concentration of serum succinate, increased renin secretion, and hypertension. These findings provide a link between kidney stone formation and hypertension through impaired transport of metabolites, and suggest that succinate and citrate signaling and transport are potential therapeutic targets. 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 expressi...