Abstract
Fibrosis contributes to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT) plays an important role in the development of fibrosis following kidney transplantation. Autophagy plays an important role in the homeostasis of diverse cell types including endothelial cells. Here we demonstrate that inhibition of autophagy by treatment with 3-methyladenine (3-MA) or by silencing autophagy-related (ATG)5 promoted interleukin (IL)-6–dependent EndMT in human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs), and autophagy inactivation was associated with EndMT in patients with chronic allograft dysfunction. IL-6 level was significantly higher in the culture medium of HUVECs transfected with ATG5 siRNA or treated with 3-MA compared to the respective control groups. IL-6 application induced EndMT in HUVECs and HRGECs, whereas antibody-mediated neutralization of IL-6 suppressed EndMT induced by ATG5 silencing. The protective role of curcumin (Cur) against allograft fibrosis was confirmed in a rat kidney transplantation model of F344 donors to Lewis recipients. Curcumin—a natural polyphenol compound with known antifibrotic effects in various tissues—alleviated IL-6–induced EndMT and promoted autophagy in the allografted organ and in HUVECs. This is the first demonstration of the role of autophagy in renal allograft fibrosis; our findings indicate that curcumin can alleviate chronic renal allograft injury by suppressing IL-6–dependent EndMT via activation of autophagy.
Highlights
Kidney transplantation is the most effective treatment for endstage renal disease
Recent studies have shown that inactivation of autophagy in endothelial cells induces interleukin (IL)-6–dependent Endothelial‐to‐ mesenchymal transition (EndMT) [29]. We investigated whether this contributes to the pathogenesis of Chronic allograft dysfunction (CAD) and examined the underlying mechanisms using human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs)
Autophagy is critical for homeostasis in cells and tissues [32, 33]; the role of autophagy in the development of renal allograft fibrosis is unknown
Summary
Kidney transplantation is the most effective treatment for endstage renal disease. Compared to dialysis, patients who undergo this procedure have a better quality or life and enhanced survival. Many cell types including endothelial cells, bone marrow mesenchymal stem cells, and peripheral blood cells transform into MFBs to promote allograft fibrosis [9,10,11]. Autophagy is an evolutionarily conserved cellular process involving the clearance of dysfunctional organelles, abnormal aggregated proteins and lipids, and pathogens that plays an important role in normal cell development, differentiation, and survival and tissue homeostasis [14, 15]. In patients with type 2 diabetes, inadequate autophagy resulted in endothelial cell dysfunction [20]; and loss of the autophagyrelated (ATG) gene accelerated diabetic nephropathy and led to renal fibrosis [21]. We evaluated whether curcumin could alleviate IL-6–dependent EndMT by promoting autophagy in vitro and in vivo using a rat kidney transplantation model
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