Kv1.3 Channel Inhibition Limits Uremia-Induced Calcification in Mouse and Human Vascular Smooth Muscle

  1. Pérez-García, Maria Teresa 1
  2. Jaisser, Frederic 2
  3. Giraldez, Teresa 3
  4. Navarro-González, Juan F 4
  5. Alvarez de la Rosa, Diego 3
  6. López-López, José R 1
  7. Cazaña-Pérez, Violeta 34
  8. Cidad, Pilar 1
  9. Rojo-Mencía, Jorge 1
  1. 1 Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
  2. 2 Unité Mixte de Recherche Scientifique 1138, Team 1, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, La Laguna, Paris, France
  3. 3 Departamento de Ciencias Médicas Básicas (Fisiología), Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Spain
  4. 4 Unidad de Investigación y Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain
Journal:
Function

ISSN: 2633-8823

Year of publication: 2021

Volume: 2

Issue: 1

Type: Article

Export: RIS
DOI: 10.1093/function/zqaa036 GOOGLE SCHOLAR lock_openOpen access editor
Author's full text: lockOpen access editor

Abstract

Abstract Chronic kidney disease (CKD) significantly increases cardiovascular risk. In advanced CKD stages, accumulation of toxic circulating metabolites and mineral metabolism alterations triggers vascular calcification, characterized by vascular smooth muscle cell (VSMC) transdifferentiation and loss of the contractile phenotype. Phenotypic modulation of VSMC occurs with significant changes in gene expression. Even though ion channels are an integral component of VSMC function, the effects of uremia on ion channel remodeling has not been explored. We used an in vitro model of uremia-induced calcification of human aorta smooth muscle cells (HASMCs) to study the expression of 92 ion channel subunit genes. Uremic serum-induced extensive remodeling of ion channel expression consistent with loss of excitability but different from the one previously associated with transition from contractile to proliferative phenotypes. Among the ion channels tested, we found increased abundance and activity of voltage-dependent K+ channel Kv1.3. Enhanced Kv1.3 expression was also detected in aorta from a mouse model of CKD. Pharmacological inhibition or genetic ablation of Kv1.3 decreased the amount of calcium phosphate deposition induced by uremia, supporting an important role for this channel on uremia-induced VSMC calcification.

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