文献类型：期刊文献

英文题名：Icariin sensitizes glucocorticoid therapy in doxorubicin-induced fibrotic nephrotic syndrome via the HIF-1α/NF-κB/HDAC2 Axis

作者：Ding, Zhaoran[1];Li, Xu[2,3];Duan, Shuwen[1];Liu, Can[4];Li, Xiaojun[5,6];Dai, Enlai[1]

第一作者：Ding, Zhaoran

通信作者：Dai, EL[1]

机构：[1]Gansu Univ Chinese Med, Sch Tradit Chinese & Western Med, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, Sci Res & Expt Ctr, Lanzhou 730000, Peoples R China;[4]Second Hosp Lanzhou Univ, Dept Tradit Chinese Med, Lanzhou 730000, Peoples R China;[5]Gansu Univ Chinese Med, Sch Basic Med Sci, Lanzhou 730000, Peoples R China;[6]Jintai Hosp Baoji City, Dept Cardiol, Baoji 721000, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Sch Tradit Chinese & Western Med, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：171

外文期刊名：INTERNATIONAL IMMUNOPHARMACOLOGY

收录：;Scopus(收录号：2-s2.0-105026685965);WOS:【SCI-EXPANDED(收录号:WOS:001662326200001)】；

基金：This work was supported by the National Natural Science Foundation of China (No.82160852) .

语种：英文

外文关键词：Nephrotic syndrome; Tubulointerstitial fibrosis; Glucocorticoid resistance; Icariin; Prednisone; HIF-1 alpha/NF-kappa B/HDAC2 axis

摘要：Nephrotic syndrome (NS) can progress to tubulointerstitial fibrosis, and a subset of patients exhibits reduced responsiveness to glucocorticoids (GCs). Beyond podocyte injury, the tubulointerstitial microenvironment may critically shape GC efficacy, but the mechanisms remain incompletely defined. We established a doxorubicin (DOX)-induced rat model featuring tubular epithelial injury with epithelial-to-mesenchymal transition (EMT), interstitial fibrosis, and a blunted therapeutic response to prednisone (Pred). We tested whether icariin (ICA) enhances GC efficacy by modulating the HIF-1 alpha/NF-kappa B/HDAC2 axis and glucocorticoid receptor (GR) signaling in DOX-induced tubular injury. Rats received ICA, Pred, ICA + Pred, tacrolimus, or the HIF-1 alpha inhibitor PX-478. We assessed proteinuria, serum biochemistry, renal histopathology, oxidative stress indices, renal microvascular perfusion, transcriptomics, and axis signaling. DOX induced severe proteinuria and renal dysfunction, accompanied by microvascular hypoperfusion and oxidative stress, together with tubular epithelial EMT and interstitial fibrosis. These changes were associated with impaired GR signaling (reduced GR expression and nuclear localization), HDAC2 downregulation, NF-kappa B activation (including increased RelA acetylation), and P-glycoprotein upregulation. Pred monotherapy conferred limited benefit, whereas ICA + Pred produced greater improvements in proteinuria, renal function, and tubulointerstitial injury, with partial normalization of tubular injury-and inflammation-enriched transcriptomic programs. ICA was associated with improved microvascular perfusion and oxidative stress indices, reduced HIF-1 alpha and P-glycoprotein expression, restored HDAC2, enhanced GR signaling, and suppression of NF-kappa B-linked inflammatory activity. PX-478 recapitulated key components of this response. Collectively, these data implicate a tubulointerstitial HIF-1 alpha/NF-kappa B/HDAC2 axis as a key contributor to blunted GC responsiveness in fibrotic NS and support ICA as a microenvironment-targeted adjunct to enhance GC efficacy.