TY - JOUR
T1 - Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease
AU - Agapova, Olga A.
AU - Fang, Yifu
AU - Sugatani, Toshifumi
AU - Seifert, Michael E.
AU - Hruska, Keith A.
N1 - Funding Information:
Thanks to Helen Odle, who assisted in preparation of the manuscript. These studies were supported by National Institutes of Health grants DK070790 (to KAH) and DK089137 (to KAH), and P30 AR057235 core center for musculoskeletal biology and medicine. Additional support was in the form of an investigator-stimulated trial grant from Celgene (to KAH).
Funding Information:
KAH declares that the work presented in this article was supported by National Institutes of Health grants DK070790 and DK089137, and by investigator-stimulated trial grants from Celgene. Celgene is developing sotatercept as a therapy for the anemia of CKD. In addition, he is an advisor for Celgene. The other authors declared no competing interests.
Publisher Copyright:
© 2016 International Society of Nephrology
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - chronic kidney disease
KW - fibrosis
KW - signaling
KW - vascular calcification
UR - http://www.scopus.com/inward/record.url?scp=84978081765&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2016.02.002
DO - 10.1016/j.kint.2016.02.002
M3 - Article
C2 - 27165838
AN - SCOPUS:84978081765
VL - 89
SP - 1231
EP - 1243
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 6
ER -