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• W2295897166 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. 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. Kidney diseases are associated with high mortality rates related to their stimulation of cardiovascular disease.1Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2874) Google Scholar The kidney disease stimulation of cardiovascular risk extends to type 2 diabetes, where the presence of mild to moderate kidney disease increases atherosclerotic cardiovascular disease risk by 87%.2Papademetriou V. Lovato L. Doumas M. et al.Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes.Kidney Int. 2015; 87: 649-659Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Atherosclerotic calcification has become a standard biomarker of cardiovascular risk,3Pletcher M.J. Tice J.A. Pignone M. et al.Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis.Arch Intern Med. 2004; 164: 1285-1292Crossref PubMed Scopus (499) Google Scholar, 4Wexler L. Brundage B. Crouse J. et al.Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications.Circulation. 1996; 94: 1175-1192Crossref PubMed Scopus (958) Google Scholar and CKD increases atherosclerotic calcification.5Barraclough K.A. Stevens L.A. Er L. et al.Coronary artery calcification scores in patients with chronic kidney disease prior to dialysis: reliability as a trial outcome measure.Nephrol Dial Transplant. 2008; 23: 3199-3205Crossref PubMed Scopus (16) Google Scholar The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease–mineral bone disorder (CKD-MBD) syndrome.6Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from kidney disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1458) Google Scholar Three nontraditional cardiovascular risk factors—hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23) levels—have been discovered in the CKD-MBD,7Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2110) Google Scholar, 8Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1234) Google Scholar, 9Gutierrez O.M. Mannstadt M. Isakova T. et al.Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis.N Engl J Med. 2008; 359: 584-592Crossref PubMed Scopus (1409) Google Scholar and their risk factor status confirmed in the general population.10Dhingra R. Sullivan L.M. Fox C.S. et al.Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Arch Intern Med. 2007; 167: 879-885Crossref PubMed Scopus (674) Google Scholar, 11Matsushita K. Sang Y. Ballew S.H. et al.Subclinical atherosclerosis measures for cardiovascular prediction in CKD.J Am Soc Nephrol. 2014; 26: 439-447Crossref PubMed Scopus (85) Google Scholar, 12Dalal M. Sun K. Cappola A.R. et al.Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women.Eur J Endocrinol. 2011; 165: 797-803Crossref PubMed Scopus (44) Google Scholar The CKD-MBD begins early in CKD (stage 2)13Fang Y. Ginsberg C. Sugatani T. et al.Early chronic kidney disease-mineral bone disorder stimulates vascular calcification.Kidney Int. 2014; 85: 142-150Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 14Pereira R.C. Juppner H. Azucena-Serrano C.E. et al.Patterns of FGF-23, DMP1 and MEPE expression in patients with chronic kidney disease.Bone. 2009; 45: 1161-1168Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 15Fang Y. Zhang Y. Mathew S. et al.Early chronic kidney disease (CKD) stimulates vascular calcification (VC) and decreased bone formation rates prior to positive phosphate balance.J Am Soc Nephrol. 2009; 20: 36AGoogle Scholar, 16Hu M.C. Shi M. Zhang J. et al.Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol. 2011; 22: 124-136Crossref PubMed Scopus (703) Google Scholar consisting of arterial vascular cell dedifferentiation and extracellular matrix calcification, an osteodystrophy, loss of klotho, and increased FGF23 secretion.13Fang Y. Ginsberg C. Sugatani T. et al.Early chronic kidney disease-mineral bone disorder stimulates vascular calcification.Kidney Int. 2014; 85: 142-150Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar Progress into the causes of the CKD-MBD has been made,16Hu M.C. Shi M. Zhang J. et al.Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol. 2011; 22: 124-136Crossref PubMed Scopus (703) Google Scholar, 17Fang Y. Ginsberg C. Seifert M. et al.CKD-induced Wingless/Integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.J Am Soc Nephrol. 2014; 25: 1760-1763Crossref PubMed Scopus (123) Google Scholar, 18de Oliveira R.B. Graciolli F.G. dos Reis L.M. et al.Disturbances of Wnt/β-catenin pathway and energy metabolism in early CKD: effect of phosphate binders.Nephrol Dial Transplant. 2013; 28: 2510-2517Crossref PubMed Scopus (39) Google Scholar, 19Sabbagh Y. Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy.J Bone Miner Res. 2012; 27: 1757-1772Crossref PubMed Scopus (189) Google Scholar but they are mostly unknown. We have employed a murine model of type 2 diabetes, atherosclerosis, and atherosclerotic calcification to demonstrate that CKD stimulates atherosclerotic calcification.20Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (179) Google Scholar, 21Mathew S. Lund R. Strebeck F. et al.Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.J Am Soc Nephrol. 2007; 18: 122-130Crossref PubMed Scopus (95) Google Scholar The development of hyperphosphatemia further stimulates the process,22El-Abbadi M.M. Pai A.S. Leaf E.M. et al.Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.Kidney Int. 2009; 75: 1297-1307Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 23Mathew S. Tustison K.S. Sugatani T. et al.The mechanism of phosphorus as a cardiovascular risk factor in chronic kidney disease.J Am Soc Nephrol. 2008; 19: 1092-1105Crossref PubMed Scopus (204) Google Scholar but is not involved in its inception, which begins much earlier in the course of CKD than hyperphosphatemia. Most recently we have focused on circulating factors produced by kidney disease that perturb normal physiological systemic processes. Multiple investigators and we have shown that kidney diseases reactivate developmental programs involved in nephrogenesis during disease-stimulated renal repair.24Surendran K. McCaul S.P. Simon T.C. A role for Wnt-4 in renal fibrosis.Am J Physiol Renal Physiol. 2002; 282: F431-F441Crossref PubMed Scopus (144) Google Scholar, 25Surendran K. Schiavi S. Hruska K.A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.J Am Soc Nephrol. 2005; 16: 2373-2384Crossref PubMed Scopus (218) Google Scholar, 26Maeshima A. Nojima Y. Kojima I. The role of the activin-follistatin system in the developmental and regeneration processes of the kidney.Cytokine Growth Factor Rev. 2001; 12: 289-298Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 27Terada Y. Tanaka H. Okado T. et al.Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats.J Am Soc Nephrol. 2003; 14: 1223-1233Crossref PubMed Scopus (134) Google Scholar, 28Kawakami T. Ren S. Duffield J.S. Wnt signalling in kidney diseases: dual roles in renal injury and repair.J Pathol. 2013; 229: 221-231Crossref PubMed Scopus (152) Google Scholar Among the nephrogenic factors reactivated in renal repair, the Wnt (portmanteau of Wingless and Integrated) family is critical for tubular epithelial reconstitution,27Terada Y. Tanaka H. Okado T. et al.Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats.J Am Soc Nephrol. 2003; 14: 1223-1233Crossref PubMed Scopus (134) Google Scholar, 28Kawakami T. Ren S. Duffield J.S. Wnt signalling in kidney diseases: dual roles in renal injury and repair.J Pathol. 2013; 229: 221-231Crossref PubMed Scopus (152) Google Scholar, 29Rinkevich Y. Montoro Daniel T. Contreras-Trujillo H. et al.In vivo clonal analysis reveals lineage-restricted progenitor characteristics in mammalian kidney development, maintenance, and regeneration.Cell Rep. 2014; 7: 1270-1283Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar and fibrosis. In the control of Wnt function, canonical signaling transcriptionally induces the expression of a family of Wnt inhibitory proteins, which are secreted proteins that serve to restrict the distances of Wnt stimulation to autocrine or paracrine factors.30Niida A. Hiroko T. Kasai M. et al.DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway.Oncogene. 2004; 23: 8520-8526Crossref PubMed Scopus (434) Google Scholar, 31Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators.Oncogene. 2006; 25: 7469-7481Crossref PubMed Scopus (776) Google Scholar, 32Reya T. Duncan A.W. Ailles L. et al.A role for Wnt signalling in self-renewal of haematopoietic stem cells.Nature. 2003; 423: 409-414Crossref PubMed Scopus (1793) Google Scholar, 33Chamorro M.N. Schwartz D.R. Vonica A. et al.FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development.EMBO J. 2004; 24: 73-84Crossref PubMed Scopus (267) Google Scholar, 34Gonzalez-Sancho J.M. Aguilera O. Garcia J.M. et al.The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer.Oncogene. 2004; 24: 1098-1103Crossref Scopus (336) Google Scholar The Wnt inhibitors are circulating factors, and the family includes the Dickkopfs (Dkk). We have shown that various forms of kidney disease increase renal expression of Wnt inhibitors including the Dkk family and increase their levels in the systemic circulation.17Fang Y. Ginsberg C. Seifert M. et al.CKD-induced Wingless/Integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.J Am Soc Nephrol. 2014; 25: 1760-1763Crossref PubMed Scopus (123) Google Scholar, 25Surendran K. Schiavi S. Hruska K.A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.J Am Soc Nephrol. 2005; 16: 2373-2384Crossref PubMed Scopus (218) Google Scholar Neutralization of a key Wnt inhibitor elevated in the circulation in CKD, Dkk1, was efficacious in the CKD-MBD. Dkk1 neutralization inhibited CKD-induced vascular dedifferentiation, vascular calcification, and renal osteodystrophy.17Fang Y. Ginsberg C. Seifert M. et al.CKD-induced Wingless/Integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.J Am Soc Nephrol. 2014; 25: 1760-1763Crossref PubMed Scopus (123) Google Scholar This effect was surprising since Wnt signaling in the vascular smooth muscle cell (VSMC) is implicated in stimulating osteoblastic transition and vascular calcification.35Al-Aly Z. Shao J.S. Lai C.F. et al.Aortic Msx2-Wnt calcification cascade is regulated by TNF-α dependent signals in diabetic Ldlr-/- mice.Arterioscler Thromb Vasc Biol. 2007; 27: 2589-2596Crossref PubMed Scopus (254) Google Scholar, 36Shao J.S. Cheng S.L. Pingsterhaus J.M. et al.Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.J Clin Invest. 2005; 115: 1210-1220Crossref PubMed Scopus (367) Google Scholar However, recent studies demonstrate that inhibition of Wnt signaling stimulates lipid accumulation in atherosclerotic plaques,37Borrell-Pagès M. Romero J.C. Badimon L. LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice.J Cell Mol Med. 2015; 19: 770-777Crossref PubMed Scopus (35) Google Scholar and that Dkk1-mediated inhibition of aortic Wnt7b stimulates Smad-mediated aortic endothelial–mesenchymal transition (EndMT) and vascular calcification.38Cheng S.-L. Shao J.-S. Behrmann A. et al.Dkk1 and Msx2–Wnt7b signaling reciprocally regulate the endothelial–mesenchymal transition in aortic endothelial cells.Arterioscler Thromb Vasc Biol. 2013; 33: 1679-1689Crossref PubMed Scopus (86) Google Scholar EndMT is a developmental physiological process involved in the development of the cardiac valves, the cardiac septum, and the aortic root,39Eisenberg L.M. Markwald R.R. Molecular regulation of atrioventricular valvuloseptal morphogenesis.Circ Res. 1995; 77: 1-6Crossref PubMed Scopus (533) Google Scholar, 40Camenisch T.D. Molin D.G.M. Person A. et al.Temporal and distinct TGFβ ligand requirements during mouse and avian endocardial cushion morphogenesis.Dev Biol. 2002; 248: 170-181Crossref PubMed Scopus (231) Google Scholar and it may41Zeisberg E.M. Tarnavski O. Zeisberg M. et al.Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.Nat Med. 2007; 13: 952-961Crossref PubMed Scopus (1620) Google Scholar or may not42Moore-Morris T. Guimarães-Camboa N. Banerjee I. et al.Resident fibroblast lineages mediate pressure overload–induced cardiac fibrosis.J Clin Invest. 2014; 124: 2921-2934Crossref PubMed Scopus (2) Google Scholar contribute to cardiac fibrosis in various adult disease states. Since EndMT is a process driven by Smad transcription factors activated by receptors for the transforming growth factor-β (TGF-β) superfamily,43Cooley B.C. Nevado J. Mellad J. et al.TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling.Sci Transl Med. 2014; 6: 227ra34Crossref PubMed Scopus (269) Google Scholar we investigated whether changes in TGF-β superfamily receptor function are involved in the pathogenesis of the CKD-MBD. Our initial strategy was to focus on the function of putatively important TGF-β superfamily receptors. The superfamily ligands generally bind to type II receptors, which associate and activate type I receptors, initiating signal transduction. Besides TGF-β receptor II (TGFβRII), bone morphogenetic protein type II receptor (BMPRII), activin receptor type IIA (ActRIIA), and activin receptor type IIB (ActRIIB) are the most important type II receptors of the superfamily. Here we report the effects of a ligand trap for the activin type IIA receptor, ActRIIA, on CKD-stimulated atherosclerotic calcification and renal αklotho levels, because the latter is a component of the CKD-MBD and has been implicated in vascular calcification.44Hu M.C. Shi M. Cho H.J. et al.Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.J Am Soc Nephrol. 2015; 26: 1290-1302Crossref PubMed Scopus (200) Google Scholar Aortic VSMC ActRIIA levels and ActRIIA signaling were decreased by CKD. The ActRIIA ligand trap increased aortic ActRIIA signaling measured by Smad activation, blocked CKD-stimulated vascular smooth muscle osteoblastic transition, and decreased atherosclerotic vascular calcification. In the kidney, we found that the ligand trap increased renal αklotho expression. Furthermore in the kidney, ActRIIA levels were not changed by CKD, and the ligand trap decreased renal ActRIIA signaling. The ligand trap also decreased renal Wnt activation and decreased circulating Dkk1. Renal fibrosis and proteinuria were decreased by the ActRIIA ligand trap. The compiled result was that RAP-011 decreased vascular calcification, and renal fibrosis. To study the effect of the ActRIIA ligand trap on the CKD-MBD in early CKD, we used the high-fat-fed ldlr–/– mouse with ablative CKD treated with a ligand trap for the receptor. The experimental design of the ActRIIA ligand trap experiments in our model is shown in Figure 1. The high-fat-fed ldlr–/– mouse is a well-characterized model of atherosclerotic vascular calcification requiring both the diet and the genotype to produce atherosclerotic vascular calcification.20Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (179) Google Scholar, 45Towler D.A. Bidder M. Latifi T. et al.Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice.J Biol Chem. 1998; 273: 30427-30434Crossref PubMed Scopus (224) Google Scholar We have used the model extensively to study stimulation of atherosclerotic calcification by CKD.13Fang Y. Ginsberg C. Sugatani T. et al.Early chronic kidney disease-mineral bone disorder stimulates vascular calcification.Kidney Int. 2014; 85: 142-150Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 17Fang Y. Ginsberg C. Seifert M. et al.CKD-induced Wingless/Integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.J Am Soc Nephrol. 2014; 25: 1760-1763Crossref PubMed Scopus (123) Google Scholar, 20Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (179) Google Scholar, 21Mathew S. Lund R. Strebeck F. et al.Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.J Am Soc Nephrol. 2007; 18: 122-130Crossref PubMed Scopus (95) Google Scholar, 23Mathew S. Tustison K.S. Sugatani T. et al.The mechanism of phosphorus as a cardiovascular risk factor in chronic kidney disease.J Am Soc Nephrol. 2008; 19: 1092-1105Crossref PubMed Scopus (204) Google Scholar, 46Davies M.R. Lund R.J. Mathew S. et al.Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.J Am Soc Nephrol. 2005; 16: 917-928Crossref PubMed Scopus (136) Google Scholar, 47Lund R.J. Davies M.R. Brown A.J. et al.Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model.J Am Soc Nephrol. 2004; 15: 359-369Crossref PubMed Scopus (89) Google Scholar, 48Mathew S. Lund R.J. Chaudhary L.R. et al.Vitamin D receptor activators can protect against vascular calcification.J Am Soc Nephrol. 2008; 19: 1509-1519Crossref PubMed Scopus (205) Google Scholar In the present studies, kidney function was reduced to approximately 30% of normal (CKD) in ldlr–/– high-fat-fed mice by renal cortical injury and contralateral nephrectomy (Supplementary Figure S1 online). The CKD mice were hyperphosphatemic (Table 1).Table 1Serum biochemical parameters in the various groups of animalsParameterGroup 1wild typeGroup 2shamGroup 3CKD-3 VGroup 4CKD-3 RMouseStrainC57BL/6ldlr–/–ldlr–/–ldlr–/–DietChowHigh fatHigh fatHigh fatSurgeryNONEShamCKDCKDWeeks postnatal28282828TreatmentNONENONEVehicleRAP-011N12151415BUN (mg/dl)24.0 ± 4.620.6 ± 3.737.7 ± 7.6aP < 0.05, groups 3 and 4 compared to group 2.36.5 ± 5.8aP < 0.05, groups 3 and 4 compared to group 2.Ca (mg/dl)8.3 ± 1.88.9 ± 0.99.4 ± 0.88.8 ± 0.3Phosphorus (mg/dl)8.9 ± 0.27.9 ± 2.311.0 ± 1.6aP < 0.05, groups 3 and 4 compared to group 2.11.8 ± 1.2aP < 0.05, groups 3 and 4 compared to group 2.BUN; blood urea nitrogen.a P < 0.05, groups 3 and 4 compared to group 2. Open table in a new tab BUN; blood urea nitrogen. Aortas from the high-fat-fed ldlr–/– mice with CKD were analyzed for TGF-β superfamily type II receptors, which are the ligand-binding component of the superfamily receptor heteromultimers composed of type II and type I (ALK) receptors. The activin type II receptor A (ActRIIA) was expressed in aortic VSMCs of the ldlr–/– high-fat-fed mice (Figure 2a and b ). CKD induced ActRIIA downregulation in the aorta (Figure 2a and b). This is consistent with internalization and degradation of ActRIIA produced by high circulating ligand levels reported in other tissues.49Simone N.D. Hall H.A. Welt C. et al.Activin regulates βA-subunit and activin receptor messenger ribonucleic acid and cellular proliferation in activin-responsive testicular tumor cells.Endocrinology. 1998; 139: 1147-1155PubMed Google Scholar, 50Liu Z.H. Tsuchida K. Matsuzaki T. et al.Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling.J Endocrinol. 2006; 189: 409-421Crossref PubMed Scopus (32) Google Scholar Endothelial cell ActRIIA was not detected by immunochemical and immunofluorescent detection (Figure 2b). The effects of CKD-induced suppression of ActRIIA levels were analyzed in aortic homogenates from CKD mice treated with vehicle or the ActRIIA ligand trap (RAP-011) (Figure 3). First, CKD-stimulated osteoblastic transition was assessed by expression of mRNA for Runx2 and alkaline phosphatase (Alpl) in the aortas of ldlr–/– high-fat-fed mice. CKD stimulated their expression, and RAP-011 treatment reversed the effects of CKD (Figure 3a). Both Runx2 expression and Alpl expression represent biomarkers of osteoblastic transition in the aorta that were reversed by RAP-011 treatment. Next, aortic mRNA of smooth muscle 22α or transgelin (Tagln), a biomarker of differentiated VSMCs,51Li L. Miano J.M. Cserjesi P. et al.SM22α, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis.Circ Res. 1996; 78: 188-195Crossref PubMed Scopus (340) Google Scholar was decreased by CKD and stimulated by RAP-011. CKD also caused decreased aortic myocardin (Myocd) mRNA expression, the VSMC-specific transcription factor, but myocardin was not affected by RAP-011 treatment. In terms of the effects of CKD and RAP-011 treatment on aortic protein levels of the respective mRNAs studied in Figure 3a, CKD increased aortic Runx2 and Alpl levels and RAP-011 normalized them (Figure 3b, data for Alpl not shown). CKD decreased the aortic levels of Tagln and α-smooth muscle actin (αSMA), another biomarker of differentiated VSMCs, and RAP-011 treatment increased them (Figure 3b, data for Tagln not shown). Myocardin levels were not changed by CKD or RAP-011 treatment. The ldlr–/– high-fat-fed mouse has atherosclerotic calcification35Al-Aly Z. Shao J.S. Lai C.F. et al.Aortic Msx2-Wnt calcification cascade is regulated by TNF-α dependent signals in diabetic Ldlr-/- mice.Arterioscler Thromb Vasc Biol. 2007; 27: 2589-2596Crossref PubMed Scopus (254) Google Scholar, 45Towler D.A. Bidder M. Latifi T. et al.Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice.J Biol Chem. 1998; 273: 30427-30434Crossref PubMed Scopus (224) Google Scholar stimulated by CKD as described previously. In the studies reported here, CKD caused accumulation of calcium deposits in the aortic atheromas in CKD vehicle-treated mice (CKD V) (Figure 4a ) and increased total tissue calcium levels (Figure 4b). Visible calcium deposits were not present in CKD mice treated with RAP-011 (CKD RAP-011), and RAP-011 decreased aortic tissue calcium content to levels observed in wild-type and sham mice, significantly below those present at the time of institution of RAP-011 treatment, the CKD group (Figure 4b). The dose of RAP-011 used here, 10 mg/kg twice weekly subcutaneously, was used to relate to prior toxicology, pharmacodynamic, and efficacy studies. Subsequent to the studies in Figure 4b, we performed a dose–response study, and equivalent or better reductions in aortic tissue calcium content resulted when doses of 5 mg/kg and 1 mg/kg twice weekly subcutaneously were used (data not shown). Despite the decrease in ActRIIA in CKD, there remained easily detected ActRIIA in the VSMCs potentially available for signaling (Figure 2b). Canonical signal transduction by the TGF-β superfamily involves ligand binding to type II receptors activating their serine/threonine kinase activity and stimulating association and phosphorylation of type I receptors, the Alk kinases (see diagrammatic representation in Supplementary Figure S2). There are 7 Alk kinases utilized by the TGF-β superfamily, and Alk4 (ActRIB) is the type I receptor most often associated with ActRIIA signaling.52Abe Y. Minegishi T. Leung P.C. Activin receptor signaling.Growth Factors. 2004; 22: 105-110Crossref PubMed Scopus (59) Google Scholar Aortic homogenates isolated from CKD mice revealed that the decrease in ActRIIA levels, which were shown quantitatively in Figure 2, were not associated with decreased tissue levels of Alk4 and Alk1 (Figure 5a ). Alk5 and Alk2, other type I receptors associated with ActRIIA signaling, were not detectable. ActRIIA activity was assessed by measuring the effect of receptor heteromultimerization, that is, phosphorylation of regulatory Smads. CKD decreased aortic phospho-Smad2/3 levels (activated Smad2/3), and RAP-011 increased them compared to CKD V, even though total Smad2/3 levels were decreased (Figure 5a and b). We also analyzed non-canonical ActRIIA signaling (Supplementary Figure S2), and found that MAP kinase (phospho-Erk1/2) was also decreased by CKD and not further affected by RAP-011 (Figure 5a), and that vascular smooth muscle levels of p38 and JNK were very low. Also, RAP-011 did not affect p-AKT levels, indicating that aortic AKT/PI3 kinase was not affected by ActRIIA signaling (data not shown). In summary, aortic ActRIIA signaling (phospho-Smad2/3) was decreased by CKD and stimulated by the ligand trap associated with suppression of osteoblastic transition in the atherosclerotic aortas by the ligand trap (Figure 3). When RAP-011 was administered to wild-type mice, the reduction in total Smad2/3 levels observed in CKD mice was reproduced (Figure 5c). However, wild-type mice had very low levels of ActRIIA and p-Smad2/3, which were" @default.
• W2295897166 created "2016-06-24" @default.
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• W2295897166 creator A5078118257 @default.
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• W2295897166 creator A5080515913 @default.
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• W2295897166 date "2016-06-01" @default.
• W2295897166 modified "2023-10-18" @default.
• W2295897166 title "Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease" @default.
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