scholarly journals Spontaneous Extracellular Matrix Accumulation in a Human in vitro Model of Renal Fibrosis Is Mediated by αV Integrins

Nephron ◽  
2019 ◽  
Vol 142 (4) ◽  
pp. 328-350 ◽  
Author(s):  
Hélène Bon ◽  
Paul Hales ◽  
Simon Lumb ◽  
Gill Holdsworth ◽  
Tim Johnson ◽  
...  
2003 ◽  
Vol 285 (1) ◽  
pp. F59-F67 ◽  
Author(s):  
Glenn A. McDonald ◽  
Pradip Sarkar ◽  
Helmut Rennke ◽  
Elaine Unemori ◽  
Raghu Kalluri ◽  
...  

Fibronectin, a large adhesive glycoprotein, is a prominent constituent of the extracellular matrix. Abnormalities in fibronectin homeostasis occur in numerous disease states, ranging from primary fibrosing conditions to neoplastic transformation. We demonstrate that fibronectin is a target protein substrate for ubiquitin-dependent degradation. Coimmunoprecipitation experiments and confocal microscopy demonstrated ubiquitin-fibronectin interaction. In an in vitro model of renal fibrosis, relaxin, an insulin-like growth factor, increased ubiquitin-dependent fibronectin degradation. Relaxin also was evaluated in an anti-glomerular basement membrane model of renal fibrosis. Animals treated with relaxin experienced renoprotection, manifested by decreased serum creatinine and proteinuria. Histological evaluation of kidney sections from animals treated with relaxin showed decreased glomerulosclerosis and interstitial fibrosis. We conclude that relaxin might be developed as a useful agent for the treatment of renal fibrosis.


Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1724
Author(s):  
Gry H. Dihazi ◽  
Marwa Eltoweissy ◽  
Olaf Jahn ◽  
Björn Tampe ◽  
Michael Zeisberg ◽  
...  

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.


1998 ◽  
Vol 45 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Paul J.Q. van der Linden ◽  
Anton F.P.M. de Goeij ◽  
Gerard A.J. Dunselman ◽  
Heleen W.H. Erkens ◽  
Johannes L.H. Evers

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e40372 ◽  
Author(s):  
Reynald M. Lescarbeau ◽  
F. Philipp Seib ◽  
Marina Prewitz ◽  
Carsten Werner ◽  
David L. Kaplan

1994 ◽  
Vol 107 (4) ◽  
pp. 1047-1053 ◽  
Author(s):  
E. van der Zee ◽  
V. Everts ◽  
K. Hoeben ◽  
W. Beertsen

The effect of interleukin-1 alpha (IL-1 alpha) and murine epidermal growth factor (EGF) on incorporation of endogenously produced collagenase in the extracellular matrix of soft connective tissue was studied in an in vitro model system using periosteal explants obtained from rabbit calvariae. Immunohistochemical analysis indicated the highest level of collagenase in explants cultured for 72 hours with IL-1 alpha in combination with EGF. Most enzyme appeared to be associated with the extracellular matrix, but labeling was also found in numerous fibroblast-like cells. Explants cultured in the presence of IL-1 alpha alone contained less enzyme and in periostea treated without cytokines, or with EGF alone, only a faint label, if any, was seen. Freshly isolated, non-cultured periostea contained no detectable enzyme. Extraction of collagenase from periostea revealed that: (1) non-cultured periosteum did not contain detectable levels of enzyme. (2) The amount of total activatable enzyme synergistically increased (10-fold) under the influence of IL-1 alpha and EGF, whereas IL-1 alpha alone showed a 4-fold enhancement compared to control or EGF-incubated explants. (3) The latent fraction of the enzyme was synergistically increased (up to 100-fold or more) in periostea cultured in the presence of IL-1 alpha + EGF (21.17 mU/explant versus 0.05 mU/explant in controls). (4) Active collagenase, on the other hand, appeared to be present in a relatively high concentration in explants cultured without cytokines (2.45 mU/explant versus 0.36 mU/explant in IL-1 alpha + EGF-treated explants).(ABSTRACT TRUNCATED AT 250 WORDS)


The Analyst ◽  
2014 ◽  
Vol 139 (12) ◽  
pp. 3039-3047 ◽  
Author(s):  
Rabee Cheheltani ◽  
Cushla M. McGoverin ◽  
Jayashree Rao ◽  
David A. Vorp ◽  
Mohammad F. Kiani ◽  
...  

FTIR-based analyses can quantify elastin and collagen in vascular tissues.


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