黄柏酮对单侧输尿管梗阻模型小鼠肾间质纤维化及铁死亡的影响-中国药房

黄柏酮对单侧输尿管梗阻模型小鼠肾间质纤维化及铁死亡的影响

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篇名：	黄柏酮对单侧输尿管梗阻模型小鼠肾间质纤维化及铁死亡的影响
TITLE：	Effects of obacunone on renal interstitial fibrosis and ferroptosis in unilateral ureteral obstruction model mice
摘要：	目的研究黄柏酮对单侧输尿管梗阻（UUO）模型小鼠肾间质纤维化的改善作用，并基于核转录因子红系2相关因子2（Nrf2）/谷胱甘肽过氧化物酶4（GPx4）信号通路介导的铁死亡探讨其作用机制。方法将30只小鼠随机分为假手术组、模型组、厄贝沙坦组（阳性对照，20mg/kg）和黄柏酮低、高剂量组（10、40mg/kg），每组6只。除假手术组外，其余各组小鼠均通过结扎单侧输尿管建立UUO模型。术后，给药组小鼠腹腔注射相应药物，假手术组、模型组小鼠腹腔注射等体积生理盐水，每天1次，连续7d。检测小鼠血清中肌酐（Cr）、血尿素氮（BUN）水平，丙二醛（MDA）含量，总超氧化物歧化酶（T-SOD）活力和肾脏组织中Fe2+浓度；苏木精-伊红（HE）染色和Masson染色观察小鼠肾脏组织形态和纤维化情况；免疫组化法检测小鼠肾脏组织中纤连蛋白（Fn）、α-平滑肌肌动蛋白（α-SMA）、GPx4、Nrf2的表达，Westernblot法和实时定量聚合酶链反应（RT-qPCR）检测小鼠肾脏组织中Fn、α-SMA、Nrf2、GPx4、溶质载体家族7成员11（SLC7A11）蛋白及mRNA的表达水平。结果与假手术组比较，模型组小鼠血清中Cr、BUN水平，MDA含量，肾脏组织中Fe2+浓度以及Fn、α-SMA蛋白和mRNA的表达水平均显著升高（P＜0.05）；血清中T-SOD活力，肾脏组织中Nrf2、GPx4、SLC7A11蛋白和mRNA的表达水平均显著降低（P＜0.05）；肾脏组织中肾小管扩张，胶原沉积明显，纤维条索较粗且着色较深，肾间质炎症细胞浸润明显。经黄柏酮干预后，小鼠血清或肾脏组织中上述指标（黄柏酮低剂量组SLC7A11mRNA除外）水平均显著逆转（P＜0.05），肾脏组织病理损伤、胶原沉积均有所减轻。结论黄柏酮可改善UUO模型小鼠的肾间质纤维化，具体作用机制可能与激活Nrf2/GPx4信号通路、抑制铁死亡有关。
ABSTRACT：	OBJECTVE To study the improvement effects of obacunone on renal interstitial fibrosis （RIF） in unilateral ureteral obstruction （UUO） model mice， and to investigate its mechanism based on ferroptosis mediated by nuclear factor erythroid 2- related factor 2（Nrf2）/glutathione peroxidase 4 （GPx4） signaling pathway. METHODS Thirty mice were randomly divided into sham operation group， model group， irbesartan group （positive control， 20 mg/kg）， obacunone low-dose and high-dose groups （10， 40 mg/kg）， with 6 mice in each group. Except for sham operation group， UUO model was established by ligation of unilateral ureter in other groups. After operation， administration groups were given intraperitoneal injection of relevant medicine， and sham operation group and model group were given intraperitoneal injection of constant volume of normal saline， once a day， for 7 consecutive days. The levels of creatinine （Cr） and blood urea nitrogen （BUN）， the content of malondialdehyde （MDA） and the activities of total superoxide dismutase （T-SOD） in serum and the concentration of Fe2+ in renal tissue were all detected. HE staining and Masson staining were performed to observe the morphology and the fibrosis of renal tissues. Immunohisto- chemical staining was used to determine expressions of the fibronectin （Fn）， α-smooth muscle actin （α-SMA）， GPx4 964083717@qq.com and Nrf2 in renal tissue. Western blot and real-time quantitative polymerase chain reaction （RT-qPCR） were used E-mail：834300205@qq.com to detect the protein and mRNA levels of Fn， α-SMA， Nrf2， GPx4 and SLC7A11 in the renal tissues. RESULTS Compared with sham operation group， serum levels of Cr and BUN， the concentration of Fe2+ in renal tissue， the protein and mRNA levels of Fn and α-SMA in model group were increased significantly （P＜0.05）， while the activity of T-SOD in serum， protein and mRNA expressions of Nrf2， GPx4， SLC7A11 in kidney tissue were significantly decreased （P＜0.05）； in the kidney tissue， the renal tubules were dilated， the collagen deposition was obvious， the fibrous bands were thicker and darker， and the renal interstitial inflammatory cells infiltrated significantly. After intervened with obacunone， the levels of above indexes （except for mRNA expression of SLC7A11 in obacunone low-dose group） in serum and renal tissue were reversed significantly （P＜0.05）， and pathological damage and collagen deposition of kidney tissue were alleviated. CONCLUSIONS Obacunone can improve renal interstitial fibrosis of UUO model mice， the mechanism of which may be associated with activating the Nrf2/GPx4 pathway and then inhibiting ferroptosis to relieve RIF in UUO model mice.
期刊：	2023年第34卷第05期
作者：	邱莎；杨丽；谭睿陟；刘建
AUTHORS：	QIU Sha，YANG Li，TAN Ruizhi，LIU Jian
关键字：	黄柏酮；肾间质纤维化；单侧输尿管梗阻；Nrf2/GPx4信号通路；铁死亡
KEYWORDS：	obacunone； renal interstitial fibrosis； unilateral ureteral obstruction； Nrf2/GPx4 signaling pathway； ferroptosis
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