title: MicroRNAs 29b, 133b, and 211 Regulate Vascular Smooth Muscle Calcification Mediated by High Phosphorus.
abstract: Vascular calcification is a frequent cause of morbidity and mortality in patients with CKD and the general population. The common association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. Because microRNAs (miRs) are involved in the transdifferentiation of vascular smooth muscle cells into osteoblast-like cells, we investigated whether miRs implicated in osteoblast differentiation and bone formation are involved in vascular calcification. Different levels of uremia, hyperphosphatemia, and aortic calcification were induced by feeding nephrectomized rats a normal or high-phosphorus diet for 12 or 20 weeks, at which times the levels of eight miRs (miR-29b, miR-125, miR-133b, miR-135, miR-141, miR-200a, miR-204, and miR-211) in the aorta were analyzed. Compared with controls and uremic rats fed a normal diet, uremic rats fed a high-phosphorous diet had lower levels of miR-133b and miR-211 and higher levels of miR-29b that correlated respectively with greater expression of osteogenic RUNX2 and with lower expression of several inhibitors of osteoblastic differentiation. Uremia per se mildly reduced miR-133b levels only. Similar results were obtained in two in vitro models of vascular calcification (uremic serum and high-calcium and -phosphorus medium), and experiments using antagomirs and mimics to modify miR-29b, miR-133b, and miR-211 expression levels in these models confirmed that these miRs regulate the calcification process. We conclude that miR-29b, miR-133b, and miR-211 have direct roles in the vascular smooth muscle calcification induced by high phosphorus and may be new therapeutic targets in the management of vascular calcification.
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain;
authors.forename: Sara
authors.initials: S
authors.lastname: Panizo
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Naves-Díaz
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain;
authors.forename: Natalia
authors.initials: N
authors.lastname: Carrillo-López
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Arias
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain;
authors.forename: José Luis
authors.initials: JL
authors.lastname: Fernández-Martín
authors.affiliation: Department of Systems Biology, Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Faculty of Medicine, University of Alcalá, Alcalá de Henares, Madrid, Spain; and.
authors.forename: María Piedad
authors.initials: MP
authors.lastname: Ruiz-Torres
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; Department of Medicine, University of Oviedo, Oviedo, Asturias, Spain cannata@hca.es irodriguez@hca.es.
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
authors.affiliation: Bone and Mineral Research Unit, Reina Sofia Institute of Renal Research (IRSIN), Renal Research Network (REDinREN) from Carlos III Health Institute (ISCIII), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; cannata@hca.es irodriguez@hca.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D003470:Culture Media; D015870:Gene Expression; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009392:Nephrectomy; D010758:Phosphorus / Q000494:pharmacology; D016226:Phosphorus, Dietary / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D014511:Uremia / Q000378:metabolism*; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism*
chemical_list: C000608867:CTNNBIP1 protein, rat; D050659:Core Binding Factor Alpha 1 Subunit; D003470:Culture Media; D047908:Intracellular Signaling Peptides and Proteins; C549446:MIRN133 microRNA, rat; C000608866:MIRN211 microRNA, rat; C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; D016226:Phosphorus, Dietary; C493717:Runx2 protein, rat; D010758:Phosphorus; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases; D002118:Calcium
keywords: cell differentiation; microRNAs; nephrectomy; primary cell culture; uremia; vascular calcification