The Secretome Analysis of Activated Human Renal Fibroblasts Revealed Beneficial Effect of the Modulation of the Secreted Peptidyl-Prolyl Cis-Trans Isomerase A in Kidney Fibrosis

• Published in: Cells (Basel, Switzerland) Switzerland), 2020-07, Vol.9 (7), p.1724
• Main Authors: Dihazi, Gry H, Eltoweissy, Marwa, Jahn, Olaf, Tampe, Björn, Zeisberg, Michael, Wülfrath, Hauke S, Müller, Gerhard A, Dihazi, Hassan
• Format: Article
• Language: English
• Subjects: Bioinformatics; Cell activation; Cell adhesion & migration; Cell culture; Cell Line, Transformed; Cell lines; Cell Survival - drug effects; Collagen; Cyclosporine - pharmacology; Cytokines; Disease Progression; Down-Regulation - drug effects; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Fibronectin; Fibronectins - metabolism; Fibrosis; Growth factors; Humans; Inflammation - pathology; Investigations; Kidney - pathology; kidney fibrosis; Kidneys; Mass spectrometry; Molecular weight; Peptides; Peptidylprolyl isomerase; Peptidylprolyl Isomerase - antagonists & inhibitors; Peptidylprolyl Isomerase - metabolism; Phenotype; Phenotypes; PPIA; Proteins; Proteome - metabolism; RNA, Small Interfering - metabolism; Scientific imaging; Secretome; Signal transduction; Software; Tacrolimus - pharmacology; transforming growth factor beta 1 (TGFβ1); Wound healing
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9071724

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.