Renal Fibrosis is Alleviated through Targeted Inhibition of Interleukin-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a pathological process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of renal fibrosis. Herein, we found that tubular aberrant expression of Interleukin (IL)-11 is critically involved in renal fibrosis. IL-11 and its receptor IL-11Rα1 were significantly induced in unilateral ureteral obstruction (UUO) kidneys and were mainly expressed by renal tubular epithelial cells (RTECs), co-localised with transforming growth factor (TGF)-β1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and TGF-β1-induced EMT in vitro. IL-11 intervention alone induced the trans-differentiation of RTECs to mesenchymal phenotype, arrested the cell cycle in G2/M phase, and increased the synthesis of pro-fibrotic mediators. The EMT response indued by IL-11 was dependent on the sequential activation of STAT3 and ERK1/2 signalling pathways, and the upregulation of metadherin (MTDH) in RTECs. Micheliolide (MCL) could competitively inhibit the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and ERK1/2/MTDH pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide (DMAMCL), a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and MCL/DMAMCL exerts its anti-fibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.