不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响

doi:10.12092/j.issn.1009-2501.2021.09.004

中国临床药理学与治疗学 ›› 2021, Vol. 26 ›› Issue (9): 995-1004.doi: 10.12092/j.issn.1009-2501.2021.09.004

不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响

占珠琴¹，白海涛²

¹厦门市儿童医院心血管内分泌血液肾脏科、厦门市新生儿疾病重点实验室，厦门 361006，福建；²厦门大学附属第一医院儿科、厦门市儿科重点实验室、厦门大学医学院儿童医学研究所，厦门 361003，福建

收稿日期:2021-02-03 修回日期:2021-08-26 出版日期:2021-09-26 发布日期:2021-09-30
通讯作者: 白海涛，女，博士，主任医师、副教授，硕士研究生导师，研究方向：小儿肾脏风湿性疾病。 Tel: 13779985336 E-mail: baihaitao@163.com
作者简介:占珠琴，女，硕士，主治医师，研究方向：小儿肾脏疾病。 Tel: 13400610601 E-mail: zhanzhuqin012103@126.com
基金资助:
福建省自然科学基金项目（2015J01549）；厦门市科技计划项目（3502Z20184017）

Effects of different doses of dexamethasone on angiotensin II, its receptors and NO levels in septic kidney injury rats

ZHAN Zhuqin ¹, BAI Haitao ²

¹ Department of Cardiovascular Endocrinology Hematology Nephrology, Xiamen Children's Hospital, Neonatal Diseases Key Laboratory of Xiamen, Xiamen 361006, Fujian, China; ² Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Pediatric Key Laboratory of Xiamen, Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen 361003, Fujian, China

Received:2021-02-03 Revised:2021-08-26 Online:2021-09-26 Published:2021-09-30

摘要/Abstract

摘要： 目的：探讨内毒素（LPS）所致脓毒症急性肾损伤（AKI）大鼠血管紧张素II（AngII）及其受体、NO表达的变化及不同剂量地塞米松（DXM）对其干预作用。方法：将Wistar大鼠随机分为5组：对照组（NC）、LPS组、三种剂量的DXM干预组（小剂量0.5 mg/kg、中剂量1.0 mg/kg、大剂量5.0 mg/kg）。AKI组通过尾静脉注射LPS，DXM干预组注射LPS后给予不同剂量的DXM，于2、6、12和24 h采集标本。HE染色观察肾组织病理，全自动生化分析仪测定血清肌酐、尿素氮，ELISA检测血清肿瘤坏死因子-α（TNF-α）、巨噬细胞炎性蛋白-1α（MIP-1α）水平；应用放射免疫分析法检测血浆及肾组织中AngII浓度变化，Western blot、免疫组化法检测肾组织血管紧张素受体1（AT1R）、血管紧张素受体2（AT2R）蛋白变化，应用硝酸还原酶法检测血清、肾组织NO变化。结果：与对照组比较，LPS组血清TNF-α、MIP-1α、肌酐、尿素氮、血浆及肾组织AngII、肾组织AT2R、血清及肾组织NO均明显升高（P<0.05），而肾组织AT1R表达明显下降（P<0.05）；病理显示LPS组出现肾小球内中性粒细胞浸润，肾小管上皮细胞肿胀、空泡变性、坏死，随着LPS作用时间的延长，病理损伤越明显；与LPS组比较，DXM干预各组血清TNF-α、MIP-1α、肌酐、尿素氮、血浆及肾组织AngII、肾组织AT2R、血清及肾组织NO下降（P<0.05），而肾组织AT1R表达明显升高（P<0.05），肾损伤病理明显减轻；其中，血清TNF-α、MIP-1α、血浆AngII以大剂量DXM干预组下降最为显著（P<0.05），血清肌酐、尿素氮、肾组织NO以小、中剂量地塞米松干预组下降更为明显（P<0.05），肾组织AngII以中剂量地塞米松干预组下降最为明显（P<0.05），肾组织AT1R以中、大剂量地塞米松组干预效果明显（P<0.05），肾组织AT2R、血清NO各地塞米松干预组差异无统计学意义。结论：LPS能诱导大鼠AKI，DXM对肾损伤具有保护作用，其作用机制可能与DXM下调炎症因子、AngII、AT2R、NO及上调AT1R表达有关，且针对不同的效应分子，不同剂量地塞米松的干预作用不同。

关键词: 血管紧张素II, 血管紧张素受体1, 血管紧张素受体2, 肾损伤, 脂多糖, 地塞米松

Abstract: AIM: To investigate the changes of angiotensin II, its receptors and nitric oxide (NO) expression in rats with acute kidney injury (AKI) induced by endotoxin (LPS) and to assess the efficacy of different doses of dexamethasone (DXM). METHODS: Wistar rats were randomly divided into five groups as follows: control group (NC), LPS group, and DXM treatment groups of different doses of DXM (0.5, 1.0 and 5.0 mg/kg). The AKI group was injected with LPS through the lateral tail vein, and the intervention group was given different doses of DXM after LPS injection. Tissue samples were collected at 2, 6, 12 and 24 h after treatment. Serum creatinine and urea nitrogen levels were determined by automatic biochemical analyzer. H&E staining was used to observe renal histopathology. Serum TNF-α and MIP-1α levels were determined by ELISA. The expression of the angiotensin receptor 1 (AT1R) and angiotensin receptor 2 (AT2R) proteins were detected by Western blot and immunohistochemistry. Nitrate reductase was used to detect NO changes in the serum and renal tissues. RESULTS: The serum levels of serum TNF-α, MIP-1α, creatinine, and urea nitrogen were significantly increased in the LPS group compared with the control group (P<0.05). A similar trend was also observed in the levels of plasma and renal tissue AngII, renal tissue AT2R, serum and renal tissue NO (P<0.05). The expression of AT1R in renal tissue was significantly decreased in the LPS group compared with the control group (P<0.05). Pathological analysis showed that glomerular neutrophil infiltration and renal tubular epithelial cells swelling, vacuolar degeneration and necrosis in the LPS group. Prolongation LPS treatment resulted in more significant kidney damage. The serum levels of TNF-α, MIP-1α, creatinine, and urea nitrogen were significantly decreased in the DXM group compared with the LPS group (P<0.05). A similar trend was also observed in the levels of plasma and renal tissue AngII, renal tissue AT2R, serum and renal tissue NO in the DXM group (P<0.05). The expression of AT1R in renal tissue was significantly increased (P<0.05) in the DXM group compared with the LPS group, indicating the alleviation of kidney injury. Amongst these biomarkers, the levels of serum TNF-α, MIP-1α, plasma AngII showed the most significant decrease in the high dose DMX group (P<0.05). The levels of serum creatinine, urea nitrogen, kidney NO showed more significant decreases in the low and medium dose DMX groups (P<0.05). The levels of kidney AngII to dose and AT1R showed the most significant decrease in medium and high dose DXM groups (P<0.05). The levels of kidney AT2R and serum NO were not significantly different between the DXM treatment groups. CONCLUSION: LPS can induce AKI in rats that can be mitigated by DXM. The mechanism of DXM in protection against AKI may be related to the down-regulation of inflammatory factors such as AngII, AT2R, and NO, and the up-regulation of AT1R expression. Different doses of dexamethasone have different intervention effects for different effector molecules.

Key words: angiotensin II, angiotensin II-type 1 receptor, angiotensin II-type 2 receptor, kidney injury, LPS, dexamethasone

中图分类号:

R965.2

占珠琴, 白海涛. 不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响[J]. 中国临床药理学与治疗学, 2021, 26(9): 995-1004.

ZHAN Zhuqin, BAI Haitao. Effects of different doses of dexamethasone on angiotensin II, its receptors and NO levels in septic kidney injury rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2021, 26(9): 995-1004.

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不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响

Effects of different doses of dexamethasone on angiotensin II, its receptors and NO levels in septic kidney injury rats

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