RT info:eu-repo/semantics/article
T1 Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation
A1 Campillo de Blas, Sofía
A1 Bohorquez Magro, María Lourdes
A1 Gutiérrez Calabrés, Elena
A1 García Ayuso, Diego
A1 Miguel, Verónica
A1 Griera Merino, Mercedes
A1 Calle, Yolanda
A1 Frutos García, Sergio de
A1 Rodríguez Puyol, Manuel Antonio
A1 Rodríguez Puyol, Diego María
A1 Calleros Basilio, Laura
AB Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins,such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction andleukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies haveindicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, weinvestigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc)and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxinsincreased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletionwith specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores,while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation andthat the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesionand podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditionalILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratorycapacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could bea potential therapeutic target for the treatment of vascular damage associated with CKD.
SN 1226-3613
YR 2022
FD 2022-03
LK http://hdl.handle.net/10017/51532
UL http://hdl.handle.net/10017/51532
LA eng
NO 13 p.
NO Ministerio de Economía y Competitividad
DS MINDS@UW
RD 19-abr-2024