Wang Yuxin, Shi Manman, Sheng Li, Ke Yanrong, Zheng Hong, Wang ChaoJun, Jiang Xiaocheng, Lu Zihan, Liu Jian, Ma Yuhua
Department of Nephrology, Traditional Chinese Medicine Hospital of Kunshan, Jiangsu, China.
Nanjing University of Chinese Medicine, Nanjing, China.
J Ethnopharmacol. 2025 Jan 31;340:119228. doi: 10.1016/j.jep.2024.119228. Epub 2024 Dec 6.
Shen-Qi-Di-Huang decoction (SQDHD) is a renowned decoction in traditional Chinese medicine, dating back to the Qing Dynasty. SQDHD has been widely applied in treating renal diseases, including Membranous nephropathy (MN), with its proven positive clinical outcomes. Nevertheless, the precise mechanism by which SQDHD exerts its therapeutic effects on MN remains uncertain.
The present research aimed to observe whether SQDHD promotes podocyte autophagy by inhibiting USP14 to increase the K63 ubiquitination of Beclin1, thereby improving MN.
An MN model was established in rats using Passive Heyman Nephritis (PHN) to explore the underlying mechanisms in vivo. The kidney function parameters were evaluated, and the histomorphology of glomerular tissues was examined. Autophagy-related protein expression was assessed using immunofluorescence staining and western blotting assays. Co-immunoprecipitation (Co-IP) was used to detect the K63 ubiquitination of Beclin1. MPC5 cells were treated in vitro with serum obtained from several rat groups. Subsequently, the expression of autophagy-related proteins, formation of autophagosomes, expression of USP14, and K63 ubiquitination of Beclin1 were quantified.
Our results demonstrated that SQDHD intervention reduced urinary protein levels, mitigated podocyte damage in MN model rats, and improved kidney tissue pathology. Furthermore, in vitro and in vivo data revealed that SQDHD therapy significantly increased podocyte autophagy, decreased USP14 expression, and raised Beclin1's K63 ubiquitination.
These results provided a scientific rationale supporting the ability of SQDHD to substantially alleviate MN progression by inducing podocyte autophagy through the inhibition of USP14 expression.
肾气地黄汤（SQDHD）是中医著名的汤剂，可追溯到清朝。SQDHD已被广泛应用于治疗肾脏疾病，包括膜性肾病（MN），临床疗效确切。然而，SQDHD对MN发挥治疗作用的确切机制仍不清楚。
本研究旨在观察SQDHD是否通过抑制USP14增加Beclin1的K63泛素化来促进足细胞自噬，从而改善MN。
采用被动海曼肾炎（PHN）建立大鼠MN模型，以探索体内潜在机制。评估肾功能参数，检查肾小球组织的组织形态学。使用免疫荧光染色和蛋白质免疫印迹法评估自噬相关蛋白表达。采用免疫共沉淀法（Co-IP）检测Beclin1的K63泛素化。用从几个大鼠组获得的血清体外处理MPC5细胞。随后，对自噬相关蛋白的表达、自噬体的形成、USP14的表达以及Beclin1的K63泛素化进行定量。
我们的结果表明，SQDHD干预降低了尿蛋白水平，减轻了MN模型大鼠的足细胞损伤，并改善了肾组织病理学。此外，体外和体内数据显示，SQDHD治疗显著增加了足细胞自噬，降低了USP14表达，并提高了Beclin1的K63泛素化。
这些结果提供了科学依据，支持SQDHD通过抑制USP14表达诱导足细胞自噬来显著缓解MN进展的能力。
