Indoxyl sulphate (IS) is a uremic toxin accumulating in the plasma of chronic kidney disease (CKD) patients. IS accumulation induces side effects in the kidneys, bones and cardiovascular system. Most studies assessed IS effects on cell lines by testing higher concentrations than those measured in CKD patients. Differently, we exposed a human microvascular endothelial cell line (HMEC-1) to the IS concentrations measured in the plasma of healthy subjects (physiological) or CKD patients (pathological). Pathological concentrations reduced cell proliferation rate but did not increase long-term oxidative stress level. Indeed, total protein thiols decreased only after 24 h of exposure in parallel with an increased Nrf-2 protein expression. IS induced actin cytoskeleton rearrangement with formation of stress fibres. Proteomic analysis supported this hypothesis as many deregulated proteins are related to actin filaments organization or involved in the endothelial to mesenchymal transition. Interestingly, two proteins directly linked to cardiovascular diseases (CVD) in in vitro and in vivo studies underwent deregulation: COP9 signalosome complex subunit 9 and thrombomodulin. Future experiments will be needed to investigate the role of these proteins and the signalling pathways in which they are involved to clarify the possible link between CKD and CVD.

Colombo, G., Astori, E., Landoni, L., Garavaglia, M.L., Altomare, A., Lionetti, M.C., et al. (2022). Effects of the uremic toxin indoxyl sulphate on human microvascular endothelial cells. JOURNAL OF APPLIED TOXICOLOGY, 42(12), 1948-1961 [10.1002/jat.4366].

Effects of the uremic toxin indoxyl sulphate on human microvascular endothelial cells

Giustarini D.;Rossi R.;
2022-01-01

Abstract

Indoxyl sulphate (IS) is a uremic toxin accumulating in the plasma of chronic kidney disease (CKD) patients. IS accumulation induces side effects in the kidneys, bones and cardiovascular system. Most studies assessed IS effects on cell lines by testing higher concentrations than those measured in CKD patients. Differently, we exposed a human microvascular endothelial cell line (HMEC-1) to the IS concentrations measured in the plasma of healthy subjects (physiological) or CKD patients (pathological). Pathological concentrations reduced cell proliferation rate but did not increase long-term oxidative stress level. Indeed, total protein thiols decreased only after 24 h of exposure in parallel with an increased Nrf-2 protein expression. IS induced actin cytoskeleton rearrangement with formation of stress fibres. Proteomic analysis supported this hypothesis as many deregulated proteins are related to actin filaments organization or involved in the endothelial to mesenchymal transition. Interestingly, two proteins directly linked to cardiovascular diseases (CVD) in in vitro and in vivo studies underwent deregulation: COP9 signalosome complex subunit 9 and thrombomodulin. Future experiments will be needed to investigate the role of these proteins and the signalling pathways in which they are involved to clarify the possible link between CKD and CVD.
2022
Colombo, G., Astori, E., Landoni, L., Garavaglia, M.L., Altomare, A., Lionetti, M.C., et al. (2022). Effects of the uremic toxin indoxyl sulphate on human microvascular endothelial cells. JOURNAL OF APPLIED TOXICOLOGY, 42(12), 1948-1961 [10.1002/jat.4366].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1230074