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| 甲基莲心碱通过抑制铁死亡改善小鼠肾脏纤维化 |
| Neferine improves renal fibrosis in mice by inhibiting ferroptosis |
| 投稿时间：2025-04-11 修订日期：2025-12-25 |
| DOI： |
| 中文关键词: 甲基莲心碱 肾脏纤维化 铁死亡 SLC7A11/GPX4通路 |
| 英文关键词:Neferine Renal fibrosis Ferroptosis SLC7A11/GPX4 pathway |
| 基金项目:宁波市卫生健康科技计划项目(2023Y40);宁波市自然科学基金(2021J024) |
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| 中文摘要: |
| 目的 观察甲基莲心碱在对腺嘌呤诱导慢性肾脏病(CKD)小鼠中的保护作用，并探讨其潜在的作用机制。方法 用0.25%腺嘌呤饲料喂养诱导CKD模型,同时予甲基莲心碱(Neferine，Nef))及铁死亡抑制剂进行干预。小鼠随机分为以下4 组，每组6只：正常组(NC)、腺嘌呤组(CKD)、腺嘌呤+甲基莲心碱组(CKD+Nef)、腺嘌呤+甲基莲心碱+铁死亡抑制剂组(CKD+Nef+erastin)。检测小鼠血清肌酐(Scr)、尿素氮(BUN)、尿酸(UA)的水平；HE和Masson染色观察肾脏病理变化；TUNEL染色法检测肾细胞死亡；普鲁士蓝染色法检测肾组织铁沉积；免疫荧光染色法检测铁死亡通路溶质载体家族7成员11(SLC7A11)、谷胱甘肽过氧化物酶4(GPX4)的表达；实时定量PCR检测肾纤维化指标α平滑肌肌动蛋白(α-SMA)、I型胶原蛋白(Collagen I)和SLC7A11，GPX4的表达。结果 与NC组相比, CKD组小鼠的Scr、BUN、UA水平均明显升高(P<0. 05)，给予Nef治疗的CKD小鼠的Scr、BUN、UA均明显下降(P<0. 05)；与CKD+Nef组相比，CKD+Nef+erastin组小鼠的Scr、BUN、UA水平升高(P<0. 05)。HE染色显示，CKD组小鼠肾小管发生损伤，肾间质明显纤维化，Nef治疗后的CKD小鼠能减轻这种病理损伤；与CKD+Nef组相比，CKD+Nef+erastin组小鼠肾脏病理损伤明显加重。Tunel染色、普鲁士蓝染色、免疫荧光染色及荧光定量PCR显示，与NC组相比，CKD组小鼠肾脏细胞死亡明显增多，肾组织铁沉积增多，SLC7A11、GPX4表达降低，α-SMA及Collagen I表达明显增高，给予Nef治疗后CKD小鼠肾脏细胞死亡及铁沉积明显减少，SLC7A11、GPX4表达明显增高，且α-SMA、Collagen I表达明显减少(P<0.05)；与CKD+Nef组相比，CKD+Nef+erastin组小鼠肾脏细胞死亡及铁沉积增多，SLC7A11、GPX4表达明显降低，α-SMA、Collagen I表达明显增高(P<0.05)。结论 甲基莲心碱可有效减轻腺嘌呤诱导的CKD 小鼠肾损伤、肾间质纤维化及铁死亡，其潜在的保护效应可能是通过调控SLC7A11/GPX4发挥作用。 |
| 英文摘要: |
| Objective To investigate the protective effects of neferine on adenine induced chronic kidney disease (CKD) in mice and explore its potential mechanisms. Methods Adenine-fed CKD model mice were randomly divided into four groups (6 per group), normal control (NC), adenosine treatment (CKD), adenosine + methylginsengine (CKD+Nef), and adenosine + methylginsengine + ferroptosis inhibitor (CKD+Nef+erastin). Serum creatinine (Scr), blood urea nitrogen (BUN), and uric acid (UA) levels were measured. Renal pathology was assessed via HE staining, renal cell death by TUNEL staining, iron deposition by Prussian blue staining, and ferroptosis pathway markers including SLC7A11 and GPX4 expression by immunofluorescence. Real-time quantitative PCR was used to analyze renal fibrosis indicators such as α-smooth muscle actin (α-SMA), type I collagen (Collagen I), and SLC7A11/GPX4. Results Compared with the NC group, CKD mice showed significantly elevated levels of Scr, BUN, and UA (P<0.05), while Nef treatment decreased (P<0.05) in CKD mice. However, CKD+Nef+erastin mice exhibited increased levels of Scr, BUN, and UA compared to CKD+Nef group (P<0.05). HE and Masson staining revealed tubular damage and significant interstitial fibrosis in CKD mice, which were mitigated by Nef treatment. In contrast, CKD+Nef+erastin mice demonstrated markedly aggravated renal pathological damage. TUNEL staining, Prussian blue staining, immunofluorescence, and real-time quantitative PCR analysis showed that CKD mice showed significantly higher renal cell death and increased iron deposition compared with NC group. SLC7A11 and GPX4 expression decreased while α-SMA and Collagen I expression increased. Nef treatment reduced both renal cell death and iron deposition in CKD mice, while SLC7A11 and GPX4 expression decreased and α-SMA and Collagen I expression increased (P<0.05). Conversely, CKD+Nef+erastin mice showed increased renal cell death and iron deposition with decreased SLC7A11 and GPX4 expression and increased α-SMA and Collagen I expression (P<0.05). Conclusion Neferine can effectively alleviate adenine-induced renal injury, renal interstitial fibrosis, and ferroptosis in CKD mice. Its potential protective effect may be mediated through the SLC7A11/GPX4 pathway. |
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