甘草酸对尿源性脓毒症相关急性肾损伤的作用机制研究

doi:10.3877/cma.j.issn.1674-3253.2025.04.017

目的

通过建立尿源性脓毒症动物模型，模拟输尿管急性梗阻感染致急性肾损伤（AKI），探讨甘草酸（GA）对尿源性脓毒症相关急性肾损伤的作用机制。

方法

将20只雄性健康新西兰兔分为四组，每组5只，即对照组、假手术组、脓毒症组、脓毒症+甘草酸组。对照组不做任何处理，仅提供饲料自由饮食。假手术组暴露左侧输尿管中上段，其他不做任何处理。脓毒症组将浓度为10⁸ cfu/mL的大肠杆菌（ATCC 25922）按0.5 mL/kg注射至家兔左侧输尿管，然后用丝线结扎输尿管的远端，复制由输尿管急性梗阻并感染致尿源性脓毒症模型。脓毒症+甘草酸组在脓毒症组的基础上经耳缘静脉注射甘草酸溶液5 mg/kg，连续给3 d。于术后72 h，检测各组外周血白细胞计数、中性粒细胞计数、C反应蛋白、血肌酐和尿素氮；采用ELISA法测定血清中高迁移率族蛋白B1（HMGB1）、肿瘤坏死因子α（TNF-α）、白介素1β（IL-1β）、白介素6（IL-6）的含量；取各组肾组织HE染色，评估炎性浸润及肾小管损伤情况；用RT-PCR、Western-blot及免疫组织化学检测肾脏中HMGB1、Toll样受体4（TLR4）、核因子κB P65（NF-κB P65）等相关信号通路分子表达。

结果

假手术组与对照组相比，血清白细胞计数、中性粒细胞计数和C反应蛋白水平含量差异无统计学意义（P>0.05）。脓毒症组血清白细胞计数、中性粒细胞计数和C反应蛋白水平显著高于假手术组（P<0.05）；GA处理72 h后脓毒症组家兔血清中白细胞、中性粒细胞和C反应蛋白的水平显著降低（P<0.05）；脓毒症组家兔血清中血肌酐和尿素氮水平显著高于假手术组（P<0.05）；GA处理72 h后脓毒症组家兔血清中血肌酐和尿素氮的水平显著降低（P<0.05）。脓毒症组家兔血清中HMGB1、TNF-α、IL-1β、IL-6水平显著高于假手术组（P<0.05）；GA处理72 h后脓毒症组家兔血清中HMGB1、TNF-α、IL-1β、IL-6水平显著降低（P<0.05）。脓毒症组家兔肾组织中的TLR4、NF-κB P65蛋白水平显著升高；GA处理后显著抑制TLR4/NF-κB信号通路激活。

结论

甘草酸对尿源性脓毒症相关AKI有一定治疗价值,甘草酸减轻尿源性脓毒症相关AKI可能是通过调控HMGB1/TLR4/NF-κB信号通路实现的。

关键词: 尿源性脓毒症, 甘草酸, 急性肾损伤, 高迁移率族蛋白B1（HMGB1）, Toll样受体4（TLR4）, 核因子κB P65（NF-κB P65）, 靶向治疗

Objective

To establish an animal model of urogenic sepsis and simulating acute kidney injury (AKI) caused by acute ureteral obstruction and infection. To explore the mechanism of action of glycyrrhizic acid (GA) on acute kidney injury related to urinary sepsis.

Methods

Twenty male healthy New Zealand rabbits were divided into four groups with five rabbits in each group: control group, sham operation group, sepsis group, sepsis + glycyrrhizin group. Control group did not receive any treatment, only with free diet. In the sham operation group, the left upper middle segment of the ureter was exposed, and no other treatment was done. In the sepsis group, E. coli (ATCC 25922) at a concentration of 10⁸ cfu/mLwas injected into the left ureter of rabbits at the rate of 0.5 mL/kg, and then the distal end of the ureter was ligated with silk suture to replicate the model of urogenic sepsis caused by acute ureteral obstruction and infection. In sepsis + glycyrrhizic acid group, on the basis of sepsis group, glycyrrhizic acid solution of 5 mg/kg was injected through ear vein for 3 consecutive days. At 72 h after operation, peripheral blood white blood cell count, neutrophil count, C-reactive protein, serum creatinine and urea nitrogen were detected. The contents of high mobility group box 1 (HMGB1), TNF-α, IL-1β and IL-6 in serum were determined by ELISA. Renal tissue of each group was stained with HE to evaluate inflammatory infiltration and renal tubular injury. The expression of HMGB1, Toll-like receptor 4 (TLR4), nuclear factor-κB P65 (NF-κB P65) and other related signaling pathways were detected by RT-PCR, Western-blot and IHC.

Results

There was no significant difference in the expression of serum leukocyte count, neutrophil count and C-reactive protein between sham operation group and control group (P>0.05). Serum leukocyte count, neutrophil count and C-reactive protein level in sepsis group were significantly higher than those in sham operation group (P<0.05). GA treatment for 72 h significantly decreased the levels of leukocytes, neutrophils and C-reactive protein in serum of rabbits in sepsis group (P<0.05). The serum creatinine and urea nitrogen levels of rabbits in sepsis group were significantly higher than those in sham operation group (P<0.05). GA treatment for 72 h reduced the serum creatinine and urea nitrogen levels of rabbits in sepsis group (P<0.05). Serum levels of HMGB1, TNF-α, IL-1β and IL-6 in sepsis group were significantly higher than those in sham operation group (P<0.05). GA treatment for 72 h reduced the serum levels of HMGB1, TNF-α, IL-1β and IL-6 of rabbits in sepsis group (P<0.05). The levels of TLR4 and NF-κB p65 in renal tissue of rabbits with sepsis were significantly increased. GA treatment significantly inhibited the activation of TLR4/NF-κB signaling pathway.

Conclusion

Glycyrrhizic acid has certain therapeutic value for AKI related to urogenic sepsis, Glycyrrhizic acid may reduce AKI associated with urogenic sepsis by regulating the HMGB1/TLR4/NF-κB signaling pathway.

Key words: Urogenic sepsis, Glycyrrhizic acid, Acute kidney injury, HMGB1, TLR4, NF-κB p65, Targeted therapy

表1 用于PCR的引物序列

引物名称	引物序列（5’-3’）
HMGB1	兔-HMGB1-S	AAGAAGTGCTCAGAGAGGTGGAAG
HMGB1	兔-HMGB1-A	GGGCGATACTCAGAACAGAACAA
TLR4	兔-TLR4-S	TAACCTGTCTAGCCTTGAGCACC
TLR4	兔-TLR4-A	ACTTCTAAACCACTCAGCCCTTG
NF-κB P65	兔-NF-κB P65-S	CGCTGGGTCCCTGAAGAATC
NF-κB P65	兔-NF-κB P65-A	GTGCTGAACACCACCGATATGT
β-actin	兔-β-actin-S	CAGCAAGCAGGAGTATGACGAGT
β-actin	兔-β-actin-A	GTCTCGTTTCTGCGCCGTTA

表1 用于PCR的引物序列

引物名称	引物序列（5’-3’）
HMGB1	兔-HMGB1-S	AAGAAGTGCTCAGAGAGGTGGAAG
HMGB1	兔-HMGB1-A	GGGCGATACTCAGAACAGAACAA
TLR4	兔-TLR4-S	TAACCTGTCTAGCCTTGAGCACC
TLR4	兔-TLR4-A	ACTTCTAAACCACTCAGCCCTTG
NF-κB P65	兔-NF-κB P65-S	CGCTGGGTCCCTGAAGAATC
NF-κB P65	兔-NF-κB P65-A	GTGCTGAACACCACCGATATGT
β-actin	兔-β-actin-S	CAGCAAGCAGGAGTATGACGAGT
β-actin	兔-β-actin-A	GTCTCGTTTCTGCGCCGTTA

表2 各组家兔血清炎性指标比较（

±s）

组别	例数	白细胞计数（10⁹/L）	C反应蛋白（mg/L）	中性粒细胞百分比（%）
对照组	5	8.4±1.8	2.1±0.4	38±6
假手术组	5	8.9±3.1	3.0±1.2	40±8
脓毒症组	5	13.9±3.1^a*	6.4±1.2^a*	59±3^a*
脓毒症+甘草酸组	5	10.2±1.5^b*	4.3±0.6^b*	50±3^b*

表2 各组家兔血清炎性指标比较（

±s）

组别	例数	白细胞计数（10⁹/L）	C反应蛋白（mg/L）	中性粒细胞百分比（%）
对照组	5	8.4±1.8	2.1±0.4	38±6
假手术组	5	8.9±3.1	3.0±1.2	40±8
脓毒症组	5	13.9±3.1^a*	6.4±1.2^a*	59±3^a*
脓毒症+甘草酸组	5	10.2±1.5^b*	4.3±0.6^b*	50±3^b*

表3 各组家兔血肌酐、尿素氮数值比较（

±s）

分组	例数	血肌酐（μmol/L）	尿素氮（mmol/L）
对照组	5	55±12	4.4±2.2
假手术组	5	62±28	5.1±1.0
脓毒症组	5	114±18^a*	9.6±0.4^a*
脓毒症+甘草酸组	5	84±10^b*	7.4±0.8^b*

表3 各组家兔血肌酐、尿素氮数值比较（

±s）

分组	例数	血肌酐（μmol/L）	尿素氮（mmol/L）
对照组	5	55±12	4.4±2.2
假手术组	5	62±28	5.1±1.0
脓毒症组	5	114±18^a*	9.6±0.4^a*
脓毒症+甘草酸组	5	84±10^b*	7.4±0.8^b*

图1 各组家兔血清中HMGB1、TNF-α、IL-1β、IL-6水平注：HMGB1为高迁移率族蛋白B1；^*P<0.05

图2 各组家兔肾组织病理光镜观察结果（HE 10×20）注：a示对照组，b示假手术组，两组无明显充血水肿和炎性细胞浸润；c示脓毒症组，见大量血症细胞浸润，肾小管上皮细胞肿胀、坏死；d示脓毒症+甘草酸组，炎症反应变化较脓毒血症组减轻

图3 各组家兔肾组织中HMGB1、TLR4、NF-κB P65 mRNA的水平注：HMGB1为高迁移率族蛋白B1；TLR4为Toll样受体4；NF-κB P65为核因子-κB P65；^*P<0.05

图4 免疫组化检测Toll样受体4（TLR4）在各组家兔肾组织中的表达（10×20）注：a示对照组，b示假手术组，两组TLR4蛋白表达量小，差异无统计学意义；c示脓毒症组，TLR4蛋白表达明显增加，d示脓毒症+甘草酸组，TLR4蛋白表达明显减少

图5 免疫组化检测核因子-κB p65（NF-κB p65）在各组家兔肾组织中的表达（10×20）注：a示对照组，b示假手术组，两组NF-κB p65蛋白表达量小，差异无统计学意义；c示脓毒症组，NF-κB p65蛋白表达明显增加，d示脓毒症+甘草酸组，NF-κB p65蛋白表达明显减少

图6 免疫组化检测各组家兔肾组织中TLR4、NF-κB p65蛋白表达水平注：^*P<0.05

图7 Western blot检测各组家兔肾组织中TLR4、NF-κB p65蛋白表达情况注：β-actin为内参

图8 Western blot检测各组家兔肾组织中TLR4、NF-κB p65蛋白表达水平注：^*P<0.05

表4 各组家兔肾组织中TLR4、NF-κB p65表达水平(

±s)

组别	TLR4	NF-κB p65
对照组	1.24+0.03	0.92+0.01
假手术组	1.25+0.02	0.93+0.02
脓毒症组	1.86+0.01^#	1.56+0.03^#
脓毒症+甘草酸组	1.47+0.02^*	1.17+0.01^*

表4 各组家兔肾组织中TLR4、NF-κB p65表达水平(

±s)

组别	TLR4	NF-κB p65
对照组	1.24+0.03	0.92+0.01
假手术组	1.25+0.02	0.93+0.02
脓毒症组	1.86+0.01^#	1.56+0.03^#
脓毒症+甘草酸组	1.47+0.02^*	1.17+0.01^*

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Study on the mechanism of glycyrrhizic acid on acute renal injury caused by urogenic sepsis

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Study on the mechanism of glycyrrhizic acid on acute renal injury caused by urogenic sepsis