title: Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease.
abstract: The causes of cardiovascular mortality associated with chronic kidney disease (CKD) are partly attributed to the CKD-mineral bone disorder (CKD-MBD). The causes of the early CKD-MBD are not well known. Our discovery of Wnt (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. In the search for such factors, we studied the effects of activin receptor type IIA (ActRIIA) signaling by using a ligand trap for the receptor, RAP-011 (a soluble extracellular domain of ActRIIA fused to a murine IgG-Fc fragment). In a mouse model of CKD that stimulated atherosclerotic calcification, RAP-011 significantly increased aortic ActRIIA signaling assessed by the levels of phosphorylated Smad2/3. Furthermore, RAP-011 treatment significantly reversed CKD-induced vascular smooth muscle dedifferentiation as assessed by smooth muscle 22α levels, osteoblastic transition, and neointimal plaque calcification. In the diseased kidneys, RAP-011 significantly stimulated αklotho levels and it inhibited ActRIIA signaling and decreased renal fibrosis and proteinuria. RAP-011 treatment significantly decreased both renal and circulating Dickkopf 1 levels, showing that Wnt activation was downstream of ActRIIA. Thus, ActRIIA signaling in CKD contributes to the CKD-MBD and renal fibrosis. ActRIIA signaling may be a potential therapeutic target in CKD.
authors.affiliation: Department of Pediatrics, Renal Division, Washington University, St. Louis, Missouri, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Agapova
authors.affiliation: Department of Pediatrics, Renal Division, Washington University, St. Louis, Missouri, USA.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Pediatrics, Renal Division, Washington University, St. Louis, Missouri, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sugatani
authors.affiliation: Department of Pediatrics, Renal Division, Washington University, St. Louis, Missouri, USA; Renal Division, Southern Illinois University, Springfield, Illinois, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Seifert
authors.affiliation: Department of Pediatrics, Renal Division, Washington University, St. Louis, Missouri, USA; Department of Cell Biology, Washington University, St. Louis, Missouri, USA; Department of Medicine, Washington University, St. Louis, Missouri, USA. Electronic address: Hruska_k@kids.wustl.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000517:prevention & control*; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005966:Glucuronidase; D006801:Humans; D007279:Injections, Subcutaneous; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007668:Kidney / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010766:Phosphorylation; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011507:Proteinuria; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D061205:Vascular Calcification / Q000097:blood / Q000517:prevention & control*
chemical_list: C000595663:ActRIIA-mIgG2aFc fusion protein; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D020011:Protective Agents; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C058992:Tagln protein, mouse; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: chronic kidney disease; fibrosis; signaling; vascular calcification