Session Name: Endothelial Cell Biology
Session Date & Time: None. Available on demand.
*Purpose: Allograft fibrosis is an important contributor to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT), dysfunction of endothelial cells, played a vital role in formation of transplanted kidney fibrosis. Src family kinases (SFKs), an important group of proto-oncogenes, were reported to play a critical role in formation of renal fibrosis. However, the effect of Src in formation of allograft kidney fibrosis remains to be determined.
*Methods: Expression of Src Kinase in CAD were examined compared with non-rejecting tissue. The long-term prognosis of CAD patients were analyzed with the Src Kinase expression. HUVECs were primarily extracted and cultured. Transforming growth factor-β1 (TGF-β1) was used to induce EndMT. Src Kinase activation was tested in cell culture. Upon silencing Src or using Src Kinase Inhibitor PP1, progression of TGF-β1 induced EndMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, were tested. By establishing rat kidney transplantation model, the protective role of PP1 in allograft fibrosis and survival rate of allo-recipients were investigated.
*Results: In this study, we found significantly higher expression of Src Kinase in CAD compared with non-rejecting tissue, and downregulation of Src Kinase was negatively related to poor prognosis in CAD patients. In addition, we observed the Src Kinase activation in transforming growth factor-β1 (TGF-β1) induced EndMT. Upon silencing Src or using Src Kinase Inhibitor PP1, progression of TGF-β1 induced EndMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Then, we found Src kinase controlled the progression of EndMT by orchestrating β-catenin signaling. By establishing rat kidney transplantation model, we confirmed the protective role of PP1 in allograft fibrosis and survival rate of allo-recipients. Then, our outcomings revealed PP1 alleviated TGF-β depended EndMT in allograft organ. In vitro study, we furtherly confirmed our vivo findings.
*Conclusions: In conclusion, to the best of our knowledge, the present study was the first to investigate the role of Src kinase in allograft kidney and suggest that PP1 blunts TGF-β1 dependent EndMT to alleviate allograft kidney fibrosis through orchestrating β-catenin signaling.
To cite this abstract in AMA style:Gui Z, Wang Z, Han Z, Tao J, Ju X, Tan R, Gu M. Src Kinase Inhibitor Pp1 Blunts Tgf-β1 Dependent Endothelial‐to‐Mesenchymal Transition to Alleviate Allograft Kidney Fibrosis Through Orchestrating β-catenin Signaling [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/src-kinase-inhibitor-pp1-blunts-tgf-%ce%b21-dependent-endothelial%e2%80%90to%e2%80%90mesenchymal-transition-to-alleviate-allograft-kidney-fibrosis-through-orchestrating-%ce%b2-catenin-signaling/. Accessed January 21, 2022.
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