Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1., Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, PR China.
College of Traditional Chinese Medicine, Chongqing Medical and Pharmaceutical College, No. 82, University Town Middle Road, Shapingba District, Chongqing, 401331, PR China.
J Ethnopharmacol. 2024 Nov 15;334:118517. doi: 10.1016/j.jep.2024.118517. Epub 2024 Jul 5.
The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored.
To elucidate the specific mechanism by which AS-IV moderates DKD progression.
A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods.
AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells.
AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.
现代医学在减轻糖尿病肾病（DKD）病理过程方面的局限性，需要新的、精确的和有效的预防和治疗方法。黄芪，是膜荚黄芪的根，在中国传统医学中用于治疗各种肾脏疾病。黄芪甲苷（AS-IV）是黄芪中的主要药理活性化合物，参与脂质代谢调节；然而，其在改善 DKD 中的肾损伤方面的潜力尚未得到探索。
阐明 AS-IV 调节 DKD 进展的具体机制。
用 AS-IV 处理 DKD 小鼠模型和高糖诱导的 HK-2 细胞。此外，进行多组学分析、分子对接和分子动力学模拟，以阐明 AS-IV 在 DKD 中的作用机制，并通过分子生物学方法进行验证。
AS-IV 调节 DKD 中的糖和脂质代谢，从而减轻肾脏中的脂质沉积。蛋白质组学分析鉴定出 12 种与 AS-IV 调节的 DKD 肾组织中脂质代谢相关的蛋白质。此外，脂质代谢组学分析显示，AS-IV 分别上调和下调了 4 种有益和 79 种有害脂质代谢物。多组学分析进一步表明，顶级差异蛋白血红素加氧酶（HMOX）1 与各种有害脂质代谢物的水平之间呈正相关，与有益脂质代谢物的水平之间呈负相关。此外，蛋白质组学分析显示，在 DKD 中用 AS-IV 治疗时，铁死亡和缺氧诱导因子（HIF）-1 信号通路的富集。验证结果表明，AS-IV 通过抑制 HIF-1α/HMOX1 通路活性、上调谷胱甘肽过氧化物酶-4 和铁蛋白重链-1 的表达以及下调酰基辅酶 A 合成酶长链家族成员-4 和转铁蛋白受体-1 的表达，有效降低了 DKD 肾小管上皮细胞中的铁死亡。我们的研究结果表明，AS-IV 通过下调 HIF-1α/HMOX1 信号通路，抑制肾小管上皮细胞的铁死亡，从而减轻 DKD 病理，是一种有前途的 DKD 治疗策略。
AS-IV 通过抑制肾小管上皮细胞中的铁死亡，为 DKD 提供了一种有前景的治疗策略。本研究的结果可能有助于促进新的治疗策略的发展。
