Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α

Abstract

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo. To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR’s effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis.

Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

“…Our previous research revealed that ATG16L‐dependent autophagy deficiency fostered the progression of EndMT and renal fibrosis after kidney transplantation 12 . Furthermore, we discovered that everolimus was capable to restoring autophagic flux, thus diminishing renal allograft interstitial fibrosis via the inhibition of the mTOR pathway 45 . In our study, we affirmed that BNIP3 knockdown negates the augmented mitophagy, and reverses the amelioration in ECM deposition and EndMT induced by Rictor ablation in endothelial cells after kidney transplantation.…”

DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis

“…Increasing evidence reveal that Akt/mTOR and NF-κB activation upregulates renal inflammation and dramatically promotes renal interstitial fibrosis and fibroblast activation [ 47 – 50 ]. And upregulation of autophagy upon PI3K/Akt/mTOR pathway inhibition can significantly stabilize IκB-α and reduce the expression of TNF-α-induced EMT [ 51 ].…”

Investigation of Anti-Epithelial-Mesenchymal Transition and Anti-Inflammation effects of Qing Fei Hua Xian Decotion on Pulmonary Fibrosis via Network Pharmacology and Experimental Verification

“…It is widely accepted that in ammation response contributes to the development of EMT, which plays a crucial role in driving the PF development [51,52]. It has been reported that TNF-α induced EMT was through activation of Akt/NF-κB (nuclear factor kappa B) pathway in a renal allograft interstitial brosis [53]. In addition, IL-1β signi cantly upregulated the expressions of MMP-2 as well as EMT markers, such as vimentin, α-SMA, bronectin [54].…”