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• W3175669393 abstract "Background : Metalloproteinases (MMPs) produced by renal fibroblasts have been implicated in the initiation and progression of calcineurin inhibitor-induced nephrotoxicity. Our lab demonstrated that loss of the calcineurin A alpha (CnAα) isoform (or presence of the calcineurin A beta (CnAβ) isoform) is associated with significantly enhanced CsA-induced MMP-9 secretion vs. in wild-type renal fibroblasts. Understanding the role of calcineurin A isoforms in the regulation of the homeostasis of extracellular matrix (ECM) degradation in the kidney after cyclosporine A (CsA) treatment needs to be further investigated. Proteomic studies in cell cultures, animal models and human tissues have contributed to our current knowledge and understanding of the pathophysiological mechanisms involved in renal fibrosis biology. Comparative proteomics characterization of our calcineurin A isoform-specific renal fibroblasts can provide new insights into MMP-9 and other protein biomarkers associated with mechanisms underlying the differential expression of CsA-induced calcineurin isoform-specific proteins associated with renal fibrosis. Objective This study uses our established CnA isoform-specific cell lines and proteomics to highlight the changes in secreted proteins associated with CsA-induced kidney fibrosis and whether those changes are calcineurin A isoform-specific. Methods and Results Wild-type (WT) and CnA α knockout (CnAα−/−) kidney fibroblast cell lines were treated with CsA at 10 ng/ml for 24 and 48 hrs in serum-free DMEM media. To characterize the CsA-induced protein profiles of our renal fibroblast cells, supernatants were collected and analyzed using a Thermo Q-Exactive HF-X Orbitrap mass spectrometer. Our results revealed that after CsA treatment for 24 hrs, significantly higher protein levels of MMP-2 and MMP-9 (3- and 6-fold, respectively) were secreted from CnAα−/− cells compared to WT cells. At 48 hrs, the levels of MMP-9 increased even higher (6.5 to 11-fold) in CnAα−/− cells vs. WT cells. However, the levels of MMP-2 in CnAα−/− cells decreased at 48 hrs. Interestingly, the proteomic profile of top proteins expressed in WT vs. CnAα−/− were differentially regulated. At 24 hrs, the top secreted proteins from WT fibroblasts were shown to be involved in regulating T-cell development and function. At 24 hrs in CnAα−/− cells, the top secreted proteins included biomarkers of structural elements of ECM (i.e. Col6, FN, Fbn1), metalloproteinases (i.e. MMP-2, MMP-9), unfolded protein response pathway and ER-stress response proteins (i.e. GRP78/BIP, ERP57, CALR), and oxidative stress pathway proteins (i.e. HYOU1, HSP7070, HSP90, PRDX1). By 48 hrs, these CsA-induced pro-fibrotic proteins were significantly upregulated in CnAα−/− cells (Range: 3- to 242-fold). Conclusions The proteomics data presented strongly confirms the differences in secreted MMP-9 and MMP-2 levels we previously demonstrated between our calcineurin A isoform-specific cell lines. Like other proteomics approaches to study renal fibrosis, we observed similar upregulated pro-fibrotic/fibrotic protein profiles. Our results also demonstrated that the upregulation of other pro-fibrotic proteins are also calcineurin A isoform specific. Support or Funding Information Funded by NIH Grant 1R15GM113120-01 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3175669393 date "2019-04-01" @default.
• W3175669393 modified "2023-09-27" @default.
• W3175669393 title "Proteomics Profiling of Cyclosporine A Treatment of Calcineurin Isoform‐Specific Renal Fibroblasts" @default.
• W3175669393 doi "https://doi.org/10.1096/fasebj.2019.33.1_supplement.lb242" @default.
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