Urea is the uremic toxin accumulating with the highest concentration in the plasma of chronic kidney disease (CKD) patients, not being completely cleared by dialysis. Urea accumulation is reported to exert direct and indirect side effects on the gastrointestinal tract, kidneys, adipocytes, and cardiovascular system (CVS), although its pathogenicity is still questioned since studies evaluating its side effects lack homogeneity. Here, we investigated the effects of physiological and pathological urea concentrations on a human endothelial cell line from the microcirculation (Human Microvascular Endothelial Cells-1, HMEC-1). Urea (5 g/L) caused a reduction in the proliferation rate after 72 h of exposure and appeared to be a potential endothelial-to-mesenchymal transition (EndMT) stimulus. Moreover, urea induced actin filament rearrangement, a significant increase in matrix metalloproteinases 2 (MMP-2) expression in the medium, and a significant up- or down-regulation of other EndMT biomarkers (keratin, fibrillin-2, and collagen IV), as highlighted by differential proteomic analysis. Among proteins whose expression was found to be significantly dysregulated following exposure of HMEC-1 to urea, dimethylarginine dimethylaminohydrolase (DDAH) and vasorin turned out to be down-regulated. Both proteins have been directly linked to cardiovascular diseases (CVD) by in vitro and in vivo studies. Future experiments will be needed to deepen their role and investigate the signaling pathways in which they are involved to clarify the possible link between CKD and CVD.

Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells / G. Colombo, A. Altomare, E. Astori, L. Landoni, M.L. Garavaglia, R. Rossi, D. Giustarini, M.C. Lionetti, N. Gagliano, A. Milzani, I. Dalle-Donne. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 24:1(2023), pp. 691.1-691.25. [10.3390/ijms24010691]

Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells

G. Colombo
Primo
;
A. Altomare
Secondo
;
E. Astori;M.L. Garavaglia;M.C. Lionetti;N. Gagliano;A. Milzani
Penultimo
;
I. Dalle-Donne
Ultimo
2023

Abstract

Urea is the uremic toxin accumulating with the highest concentration in the plasma of chronic kidney disease (CKD) patients, not being completely cleared by dialysis. Urea accumulation is reported to exert direct and indirect side effects on the gastrointestinal tract, kidneys, adipocytes, and cardiovascular system (CVS), although its pathogenicity is still questioned since studies evaluating its side effects lack homogeneity. Here, we investigated the effects of physiological and pathological urea concentrations on a human endothelial cell line from the microcirculation (Human Microvascular Endothelial Cells-1, HMEC-1). Urea (5 g/L) caused a reduction in the proliferation rate after 72 h of exposure and appeared to be a potential endothelial-to-mesenchymal transition (EndMT) stimulus. Moreover, urea induced actin filament rearrangement, a significant increase in matrix metalloproteinases 2 (MMP-2) expression in the medium, and a significant up- or down-regulation of other EndMT biomarkers (keratin, fibrillin-2, and collagen IV), as highlighted by differential proteomic analysis. Among proteins whose expression was found to be significantly dysregulated following exposure of HMEC-1 to urea, dimethylarginine dimethylaminohydrolase (DDAH) and vasorin turned out to be down-regulated. Both proteins have been directly linked to cardiovascular diseases (CVD) by in vitro and in vivo studies. Future experiments will be needed to deepen their role and investigate the signaling pathways in which they are involved to clarify the possible link between CKD and CVD.
CKD; CVD; EndMT; HMEC-1; differential proteomics; urea; vasorin
Settore BIO/06 - Anatomia Comparata e Citologia
Settore BIO/16 - Anatomia Umana
Settore CHIM/08 - Chimica Farmaceutica
   Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2018)
   UNIVERSITA' DEGLI STUDI DI MILANO
2023
30-dic-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/969598
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