Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition

作者：Li, Yaqin; Luo, Congwei; Zeng, Yiqun; Zheng, Zerong; Tao, Danping; Liu, Qiao; Hong, Yiyu; Wang, Shuo; Long, Haibo^*; Xu, Zhaozhong^*

来源：American Journal of Pathology, 2023, 193(12): 1936-1952.

DOI：10.1016/j.ajpath.2023.07.005

• TGF-BETA
• MECHANISMS
• INTERLEUKIN-11
• ACTIVATION
• MICE

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Ra1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor -01. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor -01-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Ra1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro -drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dime-thylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Ra1 interaction and blocking its downstream effects. (Am J Pathol 2023, 193: 1936-1952; https://doi.org/10.1016/ j.ajpath.2023.07.005)

• 单位
  南方医科大学