Jin Qi, Li Qian, Yang Liping, Ma Fang, Mao Huimin, Wang Yuyang, Liu Tongtong, Peng Liang, Li Ping, Zhan Yongli
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, China.
Front Pharmacol. 2025 Mar 24;16:1538061. doi: 10.3389/fphar.2025.1538061. eCollection 2025.
Renal fibrosis is an endpoint event of various progressive chronic kidney diseases (CKD), but there are no effective antifibrotic treatments. Yiqi Qingre Gao (YQQRG) has shown potential in alleviating CKD, although its exact mechanism of action remains uncertain. This study aims to evaluate the impact of YQQRG on renal fibrosis and to explore the molecular pathways involved. The study employed a unilateral ureteral obstruction (UUO) mouse model, followed by a 2-week course of YQQRG treatment. Renal function was assessed through measurements of serum creatinine (SCr) and blood urea nitrogen (BUN). Kidneys were collected for histological and molecular biology analysis. To identify the detailed mechanisms, network pharmacology, RNA sequencing (RNA-Seq), transforming growth factor-beta1 (TGF-β1)-stimulated human renal proximal tubular epithelial (HK-2) cells, and molecular docking were used. YQQRG treatment significantly improved renal function, pathological damage, and renal fibrosis in UUO mice. Ten blood-entering components and 403 potential targets of YQQRG were identified by liquid chromatography-mass spectrometry (LC-MS) and network pharmacology. 20,107 targets of renal fibrosis were revealed by RNA-Seq of kidneys from the control and UUO groups. The results of the KEGG pathway enrichment analysis of YQQRG and renal fibrosis were combined, which showed that YQQRG's renoprotective effects were strongly associated with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Experimental validation further confirmed that YQQRG suppressed the PI3K/AKT pathway in the renal tissues of UUO mice; the addition of the PI3K/AKT agonist reversed the antifibrotic effects of YQQRG in TGF-β1-stimulated HK-2 cells. Furthermore, molecular docking indicated that YQQRG's primary active components exhibited a strong binding affinity to critical targets. This study initially demonstrated that YQQRG improved renal function and kidney injury in UUO mice by revealing its antifibrotic mechanism, and it operates through the inhibition of the PI3K/AKT pathway, which highlights YQQRG as a potential therapeutic option for treating CKD.
肾纤维化是各种进行性慢性肾脏病（CKD）的终点事件，但目前尚无有效的抗纤维化治疗方法。益气清热膏（YQQRG）在缓解CKD方面已显示出潜力，但其确切作用机制仍不确定。本研究旨在评估YQQRG对肾纤维化的影响，并探索其中涉及的分子途径。该研究采用单侧输尿管梗阻（UUO）小鼠模型，随后进行为期2周的YQQRG治疗。通过测量血清肌酐（SCr）和血尿素氮（BUN）评估肾功能。收集肾脏进行组织学和分子生物学分析。为了确定详细机制，使用了网络药理学、RNA测序（RNA-Seq）、转化生长因子-β1（TGF-β1）刺激的人肾近端小管上皮（HK-2）细胞和分子对接。YQQRG治疗显著改善了UUO小鼠的肾功能、病理损伤和肾纤维化。通过液相色谱-质谱联用（LC-MS）和网络药理学鉴定出YQQRG的10种入血成分和403个潜在靶点。通过对对照组和UUO组小鼠肾脏的RNA-Seq揭示了20107个肾纤维化靶点。将YQQRG和肾纤维化的KEGG通路富集分析结果相结合，表明YQQRG的肾脏保护作用与磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）信号通路密切相关。实验验证进一步证实，YQQRG抑制了UUO小鼠肾组织中的PI3K/AKT通路；添加PI3K/AKT激动剂可逆转YQQRG在TGF-β1刺激的HK-2细胞中的抗纤维化作用。此外，分子对接表明YQQRG的主要活性成分对关键靶点具有很强的结合亲和力。本研究初步证明，YQQRG通过揭示其抗纤维化机制改善了UUO小鼠的肾功能和肾损伤，并且它通过抑制PI3K/AKT通路发挥作用，这突出了YQQRG作为治疗CKD的潜在治疗选择。
