Isoandrographolide from Andrographis paniculata ameliorates tubulointerstitial fibrosis in ureteral obstruction-induced mice, associated with negatively regulating AKT/GSK-3β/β-cat signaling pathway

• Published in: International immunopharmacology 2022-11, Vol.112, p.109201-109201, Article 109201
• Main Authors: Guan, Zhenzhen, Wang, Yaming, Xu, Haiwei, Wang, Yake, Wu, Di, Zhang, Zhizi, Liu, Zihan, Shang, Ning, Zhang, Di, Sun, Jingyang, He, Xugang, Li, Yingxue, Zhu, Lina, Liu, Zhentao, Zhang, Mingliang, Xu, Zhihao, Song, Zhe, Dai, Guifu
• Format: Article
• Language: English
• Subjects: AKT/GSK-3β/β-catenin signaling; Epithelial-mesenchymal transition; Inflammation; Isoandrographolide; Network pharmacology; Renal fibrosis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109201

[Display omitted] •Isoandrographolide exhibited lower toxicity and higher efficiency than AD on HK-2 cells.•Isoandrographolide suppressed the excessive deposition of extracellular matrix and prevented TIF.•Isoandrographolide attenuated EMT and inflammation, and thereby ameliorated TIF in UUO-induced mice.•Isoandrographolide inhibited AKT/GSK-3β/β-catenin signaling.•Isoandrographolide might be a promising lead agent to prevent and treat TIF. Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-β1 (TGF-β1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3β/β-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs.