Spontaneous Extracellular Matrix Accumulation in a Human in vitro Model of Renal Fibrosis Is Mediated by αV Integrins
Autor: | Hélène Bon, Tim Johnson, Breda Twomey, Simon Lumb, Omar Qureshi, Gill Holdsworth, Paul Hales |
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Rok vydání: | 2019 |
Předmět: |
Integrins
Cell type Integrin 030232 urology & nephrology In Vitro Techniques 030204 cardiovascular system & hematology Extracellular matrix 03 medical and health sciences 0302 clinical medicine Experimental Nephrology and Genetics: Original Paper Fibrosis Renal fibrosis Humans Medicine Fibroblast Cells Cultured biology business.industry medicine.disease Extracellular Matrix Cell biology medicine.anatomical_structure biology.protein Tubulointerstitial fibrosis Kidney Diseases business Transforming growth factor |
Zdroj: | Nephron. 142:328-350 |
ISSN: | 2235-3186 1660-8151 |
DOI: | 10.1159/000499506 |
Popis: | Background: Tubulointerstitial fibrosis is a key feature of chronic kidney diseases leading to renal failure. It is characterised by the infiltration of fibroblasts and aberrant accumulation of extracellular matrix (ECM) proteins, which are associated with progressive loss of renal function. Integrins play a major role in fibrosis, but the mechanisms through which they do this are not fully understood. Objective: Using a complex cell system, we test the hypothesis that integrins are pro-fibrotic via regulation of functional interactions between tubular epithelial cells and renal fibroblasts. Method: Contact co-culture of human primary renal proximal tubular epithelial cells and renal fibroblasts promoted the spontaneous accumulation of a mature ECM rich in interstitial collagens, which was considerably in excess of that seen in the individual mono-cultures. Both cell types persisted throughout the culture and were capable of expressing multiple ECM components. Results: While ECM accumulation was inhibited by the clinically proven anti-fibrotic, nintedanib, and was partially abrogated by transforming growth factor β neutralisation, its levels did not return to basal, indicating additional pathways were implicated in the pro-ECM response. Application of anti-integrin blocking antibodies and small molecules demonstrated a major role of the αV integrins in the ECM accumulation during fibroblast: epithelial cell interactions. Conclusion: Integrin-mediated pathways can facilitate the spontaneous accumulation of ECM during fibroblast: epithelial cell interactions, and this direct renal co-culture assay system could provide a translational in vitro assay for investigating novel pathways involved in the pro-ECM response and the screening of renal anti-fibrotic agents. |
Databáze: | OpenAIRE |
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