Modified huangfeng decoction alleviates diabetic nephropathy by activating autophagy and regulating the gut microbiota

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-20 DOI:10.1016/j.phymed.2025.156677

Yinhua Ni , Wenlong Yang , Sisi Wang , Yuxiang Pan , Haimei Du , Liujie Zheng , Cheguo Cai , Zhengwei Fu , Qiang He , Juan Jin , Peipei Zhang

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引用次数: 0

Abstract

Background

Diabetic nephropathy (DN) is one of the complications with the highest mortality among diabetes patients and can lead to renal failure. Modified Huangfeng decoction (MHD) has been widely applied in the clinical treatment of kidney diseases. However, the mechanism by which MHD affects DN has not been fully elucidated.

Purpose

To investigate the impact of MHD on DN in mice and the underlying mechanism.

Methods

The main ingredients of MHD were identified by liquid chromatography‒mass spectrometry. A high-fat diet- and streptozotocin (STZ)-induced DN mouse model was constructed and treated with MHD for 6 weeks. The serum and urine parameters were measured, and the tissue sections were histologically stained. The mRNA and protein levels of metabolism-, inflammation-, fibrosis-, and autophagy-related markers were examined by qPCR and western blotting. The microbial composition and metabolites of cecal contents were analyzed through full-length 16S rRNA sequencing and nontargeted metabolomics.

Results

MHD alleviated insulin resistance in DN mice and ameliorated changes in lipid metabolism and inflammation in the liver and fat. In addition, MHD reduced the levels of kidney injury markers in the serum and urine and attenuated inflammation and fibrosis in the kidney. These results were accompanied by enhanced gut barrier function and a markedly altered microbiota composition and metabolites, with an increased abundance of beneficial bacterial species and metabolites. Moreover, MHD itself and the microbial metabolite spermidine reduced podocyte damage by activating autophagy via the PI3K/AKT/mTOR pathway.

Conclusions

MHD potentially ameliorated DN by activating podocyte autophagy via the PI3K/AKT/mTOR pathway and modulating the gut microbiota and its metabolites. Our findings provide a more comprehensive understanding of the mechanism of MHD and the involvement of the gut‒kidney interaction in the progression of DN, laying a theoretical foundation for the clinical application of MHD in DN treatment.

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加味黄风汤通过激活自噬和调节肠道菌群减轻糖尿病肾病

背景糖尿病肾病（DN）是糖尿病患者死亡率最高的并发症之一，可导致肾功能衰竭。黄风汤加味已广泛应用于肾脏疾病的临床治疗。然而，MHD影响DN的机制尚未完全阐明。目的探讨MHD对小鼠DN的影响及其机制。方法采用液相色谱-质谱联用技术对MHD的主要成分进行鉴定。建立高脂饮食和STZ诱导的DN小鼠模型，并给予MHD治疗6周。测定血清和尿液参数，并对组织切片进行组织学染色。通过qPCR和western blotting检测代谢、炎症、纤维化和自噬相关标志物的mRNA和蛋白水平。通过全长16S rRNA测序和非靶向代谢组学分析盲肠内容物的微生物组成和代谢物。结果smhd可减轻DN小鼠的胰岛素抵抗，改善肝脏和脂肪脂质代谢和炎症的变化。此外，MHD降低了血清和尿液中肾损伤标志物的水平，减轻了肾脏的炎症和纤维化。这些结果伴随着肠道屏障功能的增强，微生物群组成和代谢物的显著改变，有益细菌种类和代谢物的丰度增加。此外，MHD本身和微生物代谢物亚精胺通过PI3K/AKT/mTOR途径激活自噬，从而减少足细胞损伤。结论smhd可能通过PI3K/AKT/mTOR通路激活足细胞自噬，调节肠道微生物群及其代谢物，从而改善DN。我们的研究结果更全面地了解了MHD的发病机制以及肠肾相互作用在DN进展中的作用，为MHD在DN治疗中的临床应用奠定了理论基础。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.