Magnolol Inhibits High Fructose-Induced Podocyte Inflammation via Downregulation of TKFC/Sp1/HDAC4/Notch1 Activation

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-10, Vol.17 (11), p.1416
• Main Authors: Zhou, Ziang, Wang, Yumeng, Xing, Yu, Pan, Shuman, Wang, Wanru, Yang, Jie, Wu, Wenyuan, Zhou, Jie, Huang, Luyi, Liang, Qiongdan, Zhang, Dongmei, Kong, Lingdong
• Format: Article
• Language: English
• Subjects: Apoptosis; Care and treatment; Creatinine; Diabetes; Diagnosis; Food habits; Fructose; Glucose; Health aspects; high fructose; Hyperuricemia; Inflammation; Kidney diseases; magnolol; NICD1; podocyte inflammation; Prevention; Proteins; Risk factors; TKFC; TNF-α; Tumor necrosis factor-TNF; Type 2 diabetes
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17111416

High fructose has been implicated as an important trigger of kidney inflammation in patients and experimental models. Magnolol, isolated from , has an anti-inflammatory effect, but its protective role in podocytes remains underexplored. This study explored the protective effects and underlying mechanism of magnolol against high fructose-induced podocyte inflammation. The effects of magnolol on high fructose-induced podocyte inflammation were assessed in male Sprague Dawley rats administered 10% ( / ) fructose water for 12 weeks and heat-sensitive human podocyte cell lines (HPCs) exposed to 5 mM fructose. Podocyte foot processes were examined using transmission electron microscopy. The expression levels of nephrin, podocin, tumor necrosis factor-α (TNF-α), Notch1 intracellular domain (NICD1), triokinase/FMN cyclase (TKFC), specificity protein 1 (Sp1) and histone deacetylase 4 (HDAC4) were determined by Western blot, immunofluorescence and real-time quantitative polymerase chain reaction (qRT-PCR). The chromatin immunoprecipitation (ChIP) assay was performed to evaluate the interaction between Sp1 and the promoter region of HDAC4. Magnolol mitigated the impairment of glomerular filtration function in high fructose-fed rats. Besides, it significantly alleviated the inflammatory responses in glomeruli and HPCs, evidenced by decreased protein levels of TNF-α and NICD1. Increased protein levels of TKFC, Sp1 and HDAC4 were observed in high fructose-stimulated HPCs and rat glomeruli. TMP195, an HDAC4 inhibitor, reduced TNF-α and NICD1 protein levels in high fructose-exposed HPCs. The increased Sp1 was shown to associate with the promoter region of HDAC4, promoting HDAC4 protein expression in high fructose-exposed HPCs. The knockdown of TKFC in HPCs by siRNA decreased Sp1, HDAC4 and NICD1 protein levels, alleviating podocyte inflammatory response. Furthermore, magnolol inhibited TKFC/Sp1/HDAC4/Notch1 activation in vivo and in vitro. Magnolol attenuated high fructose-induced podocyte inflammation possibly through the suppression of TKFC/Sp1/HDAC4/Notch1 activation, providing new evidence for its potential role in podocyte protection.