RETRACTED: Curcumin Blunts IL-6 Dependent Endothelial‐to‐Mesenchymal Transition to Alleviate Renal Allograft Fibrosis Through Autophagy Activation

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.

Natural products: potential drugs for the treatment of renal fibrosis

“…It was found that mitochondrial dysfunction was significantly improved in renal interstitial cells of UUO rats after curcumin treatment, which in turn inhibited the activation of NLRP3 inflammasome and the expression of PI3K/AKT/mTOR signaling pathway, alleviating the progression of renal fibrosis by reducing the inflammatory response and regulating autophagy [ 42 ]. Curcumin can also attenuate EndMT and fibrosis occurring after kidney transplantation, which is similarly accomplished by activating cellular autophagy [ 43 ]. In addition, curcumin can act as an anti-oxidant that can alleviate renal fibrosis induced by scavenging excess ROS, inhibiting the activity of NADPH oxidase, improving mitochondrial redox balance [ 44 ].…”

Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

“…Moreover, autophagy is reported to increase in the mice colitis model, which helps to ease inflammation (3). In another study, the antifibrotic effects of curcumin were demonstrated via its alleviation of IL-6-induced endothelial-to-mesenchymal transition through promoting autophagy in allografted organs and human umbilical vein endothelial cells (HUVECs) (117). However, it is reported that autophagy in immune cells could induce an immune response that finally aggravates fibrosis.…”

Histone modification of endothelial-mesenchymal transition in cardiovascular diseases

“…Using curcumin, a known p300 inhibitor, in vitro and in vivo , Antoinette et al ( 58 ) found that inhibition of p300 activity can reduce Smad acetylation and TGF-β activity, and reduce cardiac hypertrophy, improve diastolic function, and reduce extracellular matrix production, but not affect blood sugar. Similarly, curcumin has been shown to inhibit IL-6-dependent EndMT and attenuate renal transplant fibrosis through autophagy activation ( 59 ).…”