Abstract：
BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear.
METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed.
RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect.
CONCLUSIONS: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.
METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed.
RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect.
CONCLUSIONS: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.
摘要：
背景：原发性膜性肾病（PMN）是一种自身免疫性肾小球疾病。IL-6是PMN的潜在治疗靶标。以往的临床研究已经证明麻黄附子和参浊汤(MFSD)治疗膜性肾病的有效性。然而,MFSD的作用机制尚不清楚。
方法：检测PMN患者和健康受试者的血清IL-6水平。建立被动型Heymann肾炎(PHN)大鼠模型,采用高、低剂量MFSD进行干预,观察MFSD对肾脏病理改变及足细胞损伤的修复作用。RNA-seq用于筛选MFSD的可能靶标，结合实验结果进一步验证了MFSD靶向IL-6/STAT3的效果。最后,观察托珠单抗在PHN大鼠中的疗效.
结果：PMN患者的血清IL-6水平明显高于健康受试者。这些水平在MFSD治疗后缓解的患者中显著降低。MFSD治疗改善了PHN大鼠的实验室指标，以及肾小球滤过屏障损伤和足细胞标记蛋白的表达。肾脏转录组的变化表明，针对MFSD的差异基因富集在JAK/STAT和细胞因子相关途径中。MFSD抑制足细胞中的IL6/STAT3途径。此外,MFSD显著降低PHN大鼠血清IL-6等细胞因子水平。然而,托珠单抗治疗PHN未达到预期效果.
结论：实验性膜性肾病足细胞中IL-6/STAT3信号通路被激活。MFSD通过抑制IL-6/STAT3途径减轻足细胞损伤。
方法：检测PMN患者和健康受试者的血清IL-6水平。建立被动型Heymann肾炎(PHN)大鼠模型,采用高、低剂量MFSD进行干预,观察MFSD对肾脏病理改变及足细胞损伤的修复作用。RNA-seq用于筛选MFSD的可能靶标，结合实验结果进一步验证了MFSD靶向IL-6/STAT3的效果。最后,观察托珠单抗在PHN大鼠中的疗效.
结果：PMN患者的血清IL-6水平明显高于健康受试者。这些水平在MFSD治疗后缓解的患者中显著降低。MFSD治疗改善了PHN大鼠的实验室指标，以及肾小球滤过屏障损伤和足细胞标记蛋白的表达。肾脏转录组的变化表明，针对MFSD的差异基因富集在JAK/STAT和细胞因子相关途径中。MFSD抑制足细胞中的IL6/STAT3途径。此外,MFSD显著降低PHN大鼠血清IL-6等细胞因子水平。然而,托珠单抗治疗PHN未达到预期效果.
结论：实验性膜性肾病足细胞中IL-6/STAT3信号通路被激活。MFSD通过抑制IL-6/STAT3途径减轻足细胞损伤。
