%0 Journal Article 
%A Campillo de Blas, Sofía
%A Bohorquez Magro, María Lourdes
%A Gutiérrez Calabrés, Elena
%A García Ayuso, Diego
%A Miguel, Verónica
%A Griera Merino, Mercedes
%A Calle, Yolanda
%A Frutos García, Sergio de
%A Rodríguez Puyol, Manuel Antonio
%A Rodríguez Puyol, Diego María
%A Calleros Basilio, Laura
%T Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation
%D 2022
%@ 1226-3613
%U http://hdl.handle.net/10017/51532
%X 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 and
leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have
indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we
investigated 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 toxins
increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion
with 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 and
that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion
and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional
ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory
capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be
a potential therapeutic target for the treatment of vascular damage associated with CKD.
%~ Biblioteca Universidad de Alcala