肥胖会增加肾损伤的风险，涉及炎症、胰岛素抵抗、脂代谢紊乱、血流动力学改变等多种病理事件，是慢性肾脏病发生和进展的重要危险因素。地奥司明是一种天然黄酮苷，具有抗炎、抗氧化、抗血脂和血管舒张作用。然而，地奥司明是否对肥胖相关的肾损伤具有保护作用仍不清楚。获得了地奥司明的分子式，并筛选了地奥司明及与肥胖相关肾损伤相关的靶基因。分析了重叠靶基因之间的相互作用。对重叠的靶基因进行GO功能富集和KEGG通路富集分析。采用分子对接来评估重叠靶基因之间的结合强度。棕榈酸诱导 HK-2 细胞损伤，然后用地奥司明处理。随后，测量相关mRNA和蛋白质的表达水平。网络分析确定了219个潜在地奥司明靶基因、6800个与肥胖相关肾损伤相关的潜在靶基因和93个潜在重叠靶基因。蛋白质-蛋白质相互作用网络和分子对接结果显示，AKT1、TNF-α、SRC、EGFR、ESR1、CASP3、MMP9、PPAR-γ、GSK-3β和MMP2被确定为关键治疗靶点，并且它们与地奥司明。 GO分析表明这些关键靶点可能参与炎症、化学应激和蛋白质磷酸化。 KEGG 揭示了癌症中的信号通路、AGE-RAGE 信号通路、PI3K-AKT 信号通路、PPAR 信号通路和胰岛素抵抗对于治疗肥胖相关肾损伤至关重要。 CCK-8试验表明，地奥司明显着恢复了受棕榈酸影响的HK-2细胞的活力。油红O染色表明地奥司明显着改善棕榈酸诱导的HK-2细胞中的脂质沉积。 PCR结果显示，地奥司明抑制AKT1、TNF-α、EGFR、ESR1、CASP3、MMP9、GSK-3β和MMP2的mRNA水平，同时促进PPAR-γ的mRNA水平。 Western blot分析显示，地奥司明可恢复PPAR-γ蛋白表达，抑制NF-kB p-p65蛋白表达，并减少TNF-α蛋白表达。地奥司明在治疗肥胖相关肾损伤方面表现出多靶点、多途径作用，关键靶点包括 AKT1、TNF-α、EGFR、ESR1、CASP3、MMP9、PPAR-γ、GSK-3β 和 MMP2。该机制可能是通过调节 PPAR-γ/NF-κB 信号通路来减弱炎症反应并保护肾脏。© 2024。作者获得 Springer-Verlag GmbH 德国公司的独家许可，该公司是施普林格自然。

Obesity increases the risk of kidney injury, involving various pathological events such as inflammation, insulin resistance, lipid metabolism disorders, and hemodynamic changes, making it a significant risk factor for the development and progression of chronic kidney disease. Diosmin, a natural flavonoid glycoside, exhibits anti-inflammatory, antioxidant, anti-lipid, and vasodilatory effects. However, whether diosmin has a protective effect on obesity-related kidney injury remains unclear. The molecular formula of diosmin was obtained, and diosmin and target genes related to obesity-related kidney injury were screened. The interaction between overlapping target genes was analyzed. GO functional enrichment and KEGG pathway enrichment analyses were performed on overlapping target genes. Molecular docking was employed to assess the binding strength between overlapping target genes. Palmitic acid-induced damage to HK-2 cells, which were then treated with diosmin. Subsequently, the expression levels of relevant mRNAs and proteins were measured. Network analysis identified 219 potential diosmin target genes, 6800 potential target genes related to obesity-related kidney injury, and 93 potential overlapping target genes. Protein-protein interaction networks and molecular docking results revealed that AKT1, TNF-α, SRC, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3β, and MMP2 were identified as key therapeutic targets, and they exhibited stable binding with diosmin. GO analysis indicated that these key targets may participate in inflammation, chemical stress, and protein phosphorylation. KEGG revealed that pathways in cancer, AGE-RAGE signaling pathway, PI3K-AKT signaling pathway, PPAR signaling pathway, and insulin resistance as crucial in treating obesity-related kidney injury. CCK-8 assay showed that diosmin significantly restored the viability of HK-2 cells affected by palmitic acid. Oil Red O staining demonstrated that diosmin significantly improved lipid deposition in HK-2 cells induced by palmitic acid. PCR results showed that diosmin inhibited the mRNA levels of AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, GSK-3β, and MMP2 while promoting the mRNA level of PPAR-γ. Western blot analysis revealed that diosmin restored PPAR-γ protein expression, inhibited NF-kB p-p65 protein expression, and reduced TNF-α protein expression. Diosmin demonstrated multi-target and multi-pathway effects in the treatment of obesity-associated renal injury, with key targets including AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3β, and MMP2. The mechanism may be through the modulation of the PPAR-γ/NF-κB signaling pathway, which can attenuate inflammatory responses and protect the kidney.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.