Bortezomib limits renal allograft interstitial fibrosis by inhibiting NF-κB/TNF-α/Akt/mTOR/P70S6K/Smurf2 pathway via IκBα protein stabilization

Abstract

Chronic allograft dysfunction is a major cause of late graft failure after kidney transplantation. One of the histological changes is interstitial fibrosis, which is associated with epithelial–mesenchymal transition. Bortezomib has been reported to prevent the progression of fibrosis in organs. We used rat renal transplantation model and human kidney 2 cell line treated with tumor necrosis factor-α (TNF-α) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-α/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-α-induced epithelial–mesenchymal transition and renal allograft interstitial fibrosis in vitro and in vivo. In addition to blocking Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase/Smurf2 signaling, bortezomib’s effect on the epithelial–mesenchymal transition was associated with inhibition of nuclear factor kappa B (NF-κB) pathway by stabilizing inhibitor of NF-κB. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-κB.

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

“…The mTORC1 pathway has been linked to various diseases, 38–40 and its activation has been shown to negatively regulate renal interstitial fibrosis 16,38,41 . In our previous research, we demonstrated that the mTORC1/p70S6 kinase pathway was upregulated in renal allograft interstitial fibrosis, and inhibited with bortezomib led to a reduction in ECM deposition and mitigation of allograft interstitial fibrosis 42 . Concurrently, the influence of Rictor/mTORC2 signalling pathways on the progression of fibrotic renal disease has garnered attention.…”

“… 16 , 38 , 41 In our previous research, we demonstrated that the mTORC1/p70S6 kinase pathway was upregulated in renal allograft interstitial fibrosis, and inhibited with bortezomib led to a reduction in ECM deposition and mitigation of allograft interstitial fibrosis. 42 Concurrently, the influence of Rictor/mTORC2 signalling pathways on the progression of fibrotic renal disease has garnered attention. In mice undergoing unilateral ureter obstruction (UUO), conditional deletion of Rictor gene in fibroblasts led to a decrease in collagen deposition, cell apoptosis, and inflammatory cell infiltration, an effect which were mediated through the suppression of Akt phosphorylation.…”

The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis

“…In a classical model of lupus nephritis, the administration of MRL/lpr, which are hydrophobically modified glycol chitosan nanomicelles loaded with tacrolimus, decreased glomerulosclerosis and suppressed intrarenal inflammation via the NF-ƙB signaling pathway ( Kim et al, 2021 ). Suo et al (2021) reported that bortezomib improved renal allograft tubulointerstitial fibrosis by inhibiting the NF-ƙB-TNF-α-Akt-mTOR-P70S6K-Smurf2 pathway via IƙBα protein stabilization. Suo et al reported that TNF-α and MCP-1 expression was reduced in the renal tissue of rats with renal IRI, indicating that pioglitazone suppressed the renal IRI-induced inflammatory response by inhibiting the NF-ƙB signaling pathway ( Zou et al, 2021 ).…”

Bortezomib-loaded mixed micelles realize a “three-in-one” effect for enhanced breast cancer treatment

“…29,30 As a proteasome inhibitor, BTZ can not only kill the tumor cells through the NF-κB signaling pathway, but also can inhibit the activity of CAFs by activating caspase-3. 31,32 Moreover, BTZ was also verified to enhance the function of CD8+ T cells in the TME by regulating the expression of immune-stimulating factors. 33–37 Therefore, BTZ has potential to comprehensively regulate the TME by the “three-in-one” effect.…”