title: Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice.
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 reactive oxygen species (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, whereas Klotho reduction may aggravate the effect of IS on platelet activation in CKD andklotho+/-mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis inapoE-/-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.
authors.affiliation: Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; and.|State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Du
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Fengju
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Mengjia
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; and.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Su
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; and.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology; D005966:Glucuronidase / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D007200:Indican / Q000009:adverse effects*; D000090265:Klotho Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005966:Glucuronidase; D000090265:Klotho Proteins; D007200:Indican