Hydrangea paniculata coumarins alleviate adriamycin-induced renal lipotoxicity through activating AMPK and inhibiting C/EBPβ

Yuanyuan Chen; Xikun Liu; Jie Ma; Weida Wang; Zhaojun Li; Haijie Wu; Zhanxi Lu; Dongming Zhang; Xiaoying Zhang; Yu Zhang; Sen Zhang

doi:10.1016/j.jep.2024.118156

Hydrangea paniculata coumarins alleviate adriamycin-induced renal lipotoxicity through activating AMPK and inhibiting C/EBPβ

J Ethnopharmacol. 2024 Apr 5:329:118156. doi: 10.1016/j.jep.2024.118156. Online ahead of print.

Authors

Yuanyuan Chen¹, Xikun Liu¹, Jie Ma¹, Weida Wang¹, Zhaojun Li¹, Haijie Wu¹, Zhanxi Lu², Dongming Zhang¹, Xiaoying Zhang³, Yu Zhang⁴, Sen Zhang⁵

Affiliations

¹ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, PR China.
² Beijing No. 80 High School International Department, Beijing, 100102, PR China.
³ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, PR China. Electronic address: xiaoyingzhang@imm.ac.cn.
⁴ Department of Orthopaedics, The First People's Hospital of Chengdu, Chengdu, Sichuan Province, 610041, PR China. Electronic address: 52032849@qq.com.
⁵ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, PR China. Electronic address: zhangs@imm.ac.cn.

PMID: 38583729
DOI: 10.1016/j.jep.2024.118156

Abstract

Ethnopharmacological relevance: Throughout Chinese history, Hydrangea paniculata Siebold has been utilized as a traditional medicinal herb to treat a variety of ailments associated to inflammation. In a number of immune-mediated kidney disorders, total coumarins extracted from Hydrangea paniculata (HP) have demonstrated a renal protective effect.

Aim of the study: To investigate renal beneficial effect of HP on experimental Adriamycin nephropathy (AN), and further clarify whether reversing lipid metabolism abnormalities by HP contributes to its renoprotective effect and find out the underlying critical pathways.

Materials and methods: After establishment of rat AN model, HP was orally administrated for 6 weeks. Biochemical indicators related to kidney injury were determined. mRNAs sequencing using kidney tissues were performed to clarify the underlying mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, western blot, molecular docking, and drug affinity responsive target stability (DARTS) assay was carried out to further explore and confirm pivotal molecular pathways and possible target by which HP and 7-hydroxylcoumarin (7-HC) played their renal protection effect via modulating lipid metabolism.

Results: HP could significantly improve renal function, and restore renal tubular abnormal lipid metabolism and interstitial fibrosis in AN. In vitro study demonstrated that HP and its main metabolite 7-HC could reduce ADR-induced intracellular lipid deposition and fibrosis characteristics in renal tubular cells. Mechanically, HP and 7-HC can activate AMP-activated protein kinase (AMPK) via direct interaction, which contributes to its lipid metabolism modulation effect. Moreover, HP and 7-HC can inhibit fibrosis by inhibiting CCAAT/enhancer binding protein beta (C/EBPβ) expression in renal tubular cells. Normalization of lipid metabolism by HP and 7-HC further provided protection of mitochondrial structure integrity and inhibited the nuclear factor kappa-B (NF-κB) pathway. Long-term toxicity using beagle dogs proved the safety of HP after one-month administration.

Conclusion: Coumarin derivates from HP alleviate adriamycin-induced lipotoxicity and fibrosis in kidney through activating AMPK and inhibiting C/EBPβ.

Keywords: AMPK; Adriamycin nephropathy; C/EBPβ; Coumarins; Hydrangea paniculata; Lipid metabolism.