Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation

Kidney disease: Enzyme linked to cardiovascular complications An enzyme involved in organizing structural proteins into protrusions of the cell membrane helps facilitate the movement of white blood cells that occurs in chronic kidney disease and can lead to cardiovascular damage. Laura Calleros from the University of Alcala, Madrid, Spain, and colleagues showed how toxic metabolites that build up in the bloodstream as kidneys fail induce the activity of an enzyme called integrin-linked kinase (ILK). This enzyme in turn spurs white blood cells to form protrusions called podosomes that make the cells more mobile, enabling them to move out of blood vessels and into surrounding tissues where they can cause inflammation -mediated injury. ILK inactivation reversed these effects. Therapies that target the enzyme could therefore help limit the cardiovascular complications of chronic kidney disease. 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.

Automated summary

Chronic kidney disease can lead to cardiovascular damage, and a study has identified an enzyme called integrin-linked kinase (ILK) that plays a role in this process. ILK stimulates the formation of protrusions in white blood cells, causing them to become more mobile and potentially causing inflammation-mediated injury. Inactivating ILK can reverse these effects, suggesting that targeting this enzyme could help reduce cardiovascular complications associated with chronic kidney disease.