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Uremic solute indoxyl sulfate-induced platelet hyperactivity contributes to CKD-associated thrombosis in mice

Ke Yang, Changhong Du, Xinmiao Wang, Fengju Li, Yang Xu, Song Wang, Shilei Chen, Fang Chen, Mingqiang Shen, Mo Chen, Mengjia Hu, Ting He, Yongping Su, Junping Wang and Jinghong Zhao

Key points

  • Uremic solute indoxyl sulfate increases platelet activity via activation of ROS/p38MAPK signaling.

  • Klotho counteracts indoxyl sulfate-induced thrombosis by restraining platelet hyperactivity.

Abstract

Thrombosis is a common complication of chronic kidney disease (CKD), but the causes and mechanisms of CKD-associated thrombosis are not well clarified. Here, we show that platelet activity is remarkably enhanced in CKD mice, with increase of serum indoxyl sulfate (IS), a typical uremic toxin which cannot be effectively cleared by routine dialysis. Ex vivo and in vitro experiments reveal that IS displays a distinct ability to enhance platelet activities, including elevated response to collagen and thrombin, increases in platelet-derived microparticles and platelet-monocyte aggregates. The flow chamber assay and carotid artery thrombosis model demonstrate that IS-induced platelet hyperactivity contributes to thrombus formation. Further investigations disclose that ROS-mediated p38MAPK signaling plays a key role in IS-induced platelet hyperactivity. Moreover, we show that Klotho, which is expressed dominantly in the kidneys, has the capacity to counteract IS-induced platelet hyperactivity by inhibiting ROS/p38MAPK signaling, while Klotho reduction may aggravate the effect of IS on platelet activation in CKD and klotho+/- mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis in apoE-/- mice. Our findings uncover the mechanism of platelet hyperactivity induced by IS and provide new insights into the pathogenesis and treatment of CKD-associated thrombosis.

  • Submitted October 6, 2016.
  • Accepted February 28, 2017.