Abstract
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.
Highlights
Cellular proteins exported into extracellular fluids represent a major class of proteins, collectively referred to as the secretome [1,2]
Similar results could be observed when we investigated the secretome of the fibrotic cell line TK188, where the level of peptidyl-prolyl cis-trans isomerase A (PPIA) was significantly higher compared to the level in TK173 secretome (Figure S4A,B) suggesting a potential role of PPIA in renal fibrosis
Fibroblast-to-myofibroblast transition, characterized by excessive extracellular matrix (ECM) production and deposition, plays a critical role in fibrogenesis and count to the driving forces of renal fibrosis [38,39,40,41]. We reported that this transformation of renal cells toward fibrotic phenotype is accompanied by alteration in renal cell secretome [4,21,32,33], which may result in stimulation of other cells and amplification of fibrosis
Summary
Cellular proteins exported into extracellular fluids represent a major class of proteins, collectively referred to as the secretome [1,2]. The transition of kidney cells during fibrosis does result in extensive production and secretion of ECM and in global alteration in the composition of secreted proteins [18], which is reflected in the secretion of a broad range of proinflammatory and profibrotic paracrine mediators, such as transforming growth factor beta (TGFβ) [18]. Such secreted mediators and amplifiers of fibrosis are potential therapeutic targets in the management of organ fibrosis. Due to the central role of secreted proteins in organ disease onset and progression, secretome investigations have received considerable in recent years
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