Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells
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 cardi...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/1/691 |
| _version_ | 1797625538192343040 |
|---|---|
| author | Graziano Colombo Alessandra Altomare Emanuela Astori Lucia Landoni Maria Lisa Garavaglia Ranieri Rossi Daniela Giustarini Maria Chiara Lionetti Nicoletta Gagliano Aldo Milzani Isabella Dalle-Donne |
| author_facet | Graziano Colombo Alessandra Altomare Emanuela Astori Lucia Landoni Maria Lisa Garavaglia Ranieri Rossi Daniela Giustarini Maria Chiara Lionetti Nicoletta Gagliano Aldo Milzani Isabella Dalle-Donne |
| author_sort | Graziano Colombo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T09:57:47Z |
| format | Article |
| id | doaj.art-52291e04120e4c3bbfe4d5d3877de6d2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:57:47Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-52291e04120e4c3bbfe4d5d3877de6d22023-11-16T15:37:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124169110.3390/ijms24010691Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial CellsGraziano Colombo0Alessandra Altomare1Emanuela Astori2Lucia Landoni3Maria Lisa Garavaglia4Ranieri Rossi5Daniela Giustarini6Maria Chiara Lionetti7Nicoletta Gagliano8Aldo Milzani9Isabella Dalle-Donne10Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Pharmaceutical Sciences, Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018–2022), University of Siena, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018–2022), University of Siena, 53100 Siena, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyDepartment of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, 20133 Milan, ItalyUrea 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.https://www.mdpi.com/1422-0067/24/1/691ureaHMEC-1CVDCKDvasorindifferential proteomics |
| spellingShingle | Graziano Colombo Alessandra Altomare Emanuela Astori Lucia Landoni Maria Lisa Garavaglia Ranieri Rossi Daniela Giustarini Maria Chiara Lionetti Nicoletta Gagliano Aldo Milzani Isabella Dalle-Donne Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells International Journal of Molecular Sciences urea HMEC-1 CVD CKD vasorin differential proteomics |
| title | Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells |
| title_full | Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells |
| title_fullStr | Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells |
| title_full_unstemmed | Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells |
| title_short | Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells |
| title_sort | effects of physiological and pathological urea concentrations on human microvascular endothelial cells |
| topic | urea HMEC-1 CVD CKD vasorin differential proteomics |
| url | https://www.mdpi.com/1422-0067/24/1/691 |
| work_keys_str_mv | AT grazianocolombo effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT alessandraaltomare effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT emanuelaastori effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT lucialandoni effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT marialisagaravaglia effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT ranierirossi effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT danielagiustarini effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT mariachiaralionetti effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT nicolettagagliano effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT aldomilzani effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells AT isabelladalledonne effectsofphysiologicalandpathologicalureaconcentrationsonhumanmicrovascularendothelialcells |