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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.