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

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.

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

“…Renal fibroblasts quiescently reside in renal interstitium and play an essential role in ECM homeostasis for maintaining the kidney ultrastructure and function 61 , 62 . During fibrogenesis, the quiescent fibroblasts are activated and display a spindle-shaped, mesenchymal phenotype, known as myofibroblasts 63 , 64 .…”

Macrophage Ontogeny, Phenotype, and Function in Ischemia Reperfusion-Induced Injury and Repair

“… 96 Excessive production of this cytokine over time drives the accumulation of myofibroblasts, cells that deposit large amounts of ECM proteins, including collagens (Figure 3 ). 97 , 98 The exact precursor cell that gives rise to myofibroblasts is not well understood, although it has been proposed that they may arise from epithelial to mesenchymal transition, endothelial to mesenchymal transition, fibrocyte recruitment, pericyte recruitment, and resident fibroblast recruitment. 99 TGF- β pathway activation also results in activation of the NLRP3, Smad3, and Caspase-1 stimulators, which further exacerbate renal fibrosis.…”

Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy

“…Myofibroblasts will continue to produce more ECM components. Consequently, the imbalance of ECM synthesis and degradation promotes the deposition of ECM components in the kidney, thereby induing glomerular sclerosis and renal fibrosis ( 42 ). Studies have confirmed that renal fibrosis is the common pathological process during the progression of AKI to CKD ( 43 ).…”