Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease.
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.
['Agapova|Olga A|OA|', 'Fang|Yifu|Y|', 'Sugatani|Toshifumi|T|', 'Seifert|Michael E|ME|', 'Hruska|Keith A|KA|']
D030301:Activin Receptors, Type II D000818:Animals D001011:Aorta D050197:Atherosclerosis D012080:Chronic Kidney Disease-Mineral and Bone Disorder D004195:Disease Models, Animal D005355:Fibrosis D005966:Glucuronidase D006801:Humans D007279:Injections, Subcutaneous D036341:Intercellular Signaling Peptides and Proteins D007668:Kidney D000090265:Klotho Proteins D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008840:Microfilament Proteins D009124:Muscle Proteins D010766:Phosphorylation D020011:Protective Agents D011507:Proteinuria D011956:Receptors, Cell Surface D011993:Recombinant Fusion Proteins D015398:Signal Transduction D051899:Smad2 Protein D051900:Smad3 Protein D061205:Vascular Calcification
fibrosis chronic kidney disease signaling vascular calcification