参芪泄浊饮通过调控Rap1/MAPK/FoxO3a信号通路改善氧化应激及炎症反应延缓大鼠肾纤维化

doi:10.12122/j.issn.1673-4254.2025.12.06

摘要/Abstract

摘要：

目的明确参芪泄浊饮（SQXZD）的化学成分，并结合网络药理学及实验阐明SQXZD延缓大鼠肾纤维化的作用机制。方法通过Q Exactive高分辨液质联用系统（UPLC-Q Exactive/MS）鉴定SQXZD化学成分。基于SQXZD化学成分构建SQXZD延缓肾纤维化的成分-疾病靶点网络，并进行富集分析以筛选关键通路与作用靶标。将49只SPF级雄性SD大鼠随机分成空白组，假手术组，模型组，氯沙坦组（4.6 mg·kg^-1·d^-1）及SQXZD低、中、高剂量组（9.7、19.4、38.8 g·kg^-1·d^-1）。除空白组及假手术组，其他组大鼠均以单侧输尿管结扎法复制肾纤维化模型。造模成功并连续灌胃14 d后取材，HE染色观察术侧肾组织病理变化，Masson染色观察术侧肾组织胶原沉积面积，全自动生化分析仪检测血清BUN、Cr水平，ELISA法检测血清SOD、MDA、GSH-px、IL-6、TNF‑α水平；Western blotting及qRT-PCR检测各组大鼠术侧肾组织α-SMA、Col-Ⅰ、NAKED2、Rap1、B-raf、Raf-1、MEK3/6、p38MAPK、MEK、ERK1/2、p-ERK1/2、FoxO3a、p-FoxO3a及MnSOD表达及mRNA转录水平。结果从SQXZD中鉴定出263种化学成分；网络药理学获得SQXZD成分和肾纤维化疾病交集靶点170个，分析显示SQXZD延缓肾纤维化可能与MAPK、Rap1、FoxO等通路相关。动物实验显示，与假手术组比较，模型组大鼠术侧肾组织结构异常、纤维化面积扩大；血清BUN、Cr、MDA、IL-6、TNF-α水平升高（P<0.01），SOD及GSH-px水平下降（P<0.01）；术侧肾组织α-SMA、Col-Ⅰ、NAKED2、Rap1、B-raf、MEK、ERK1/2、p-ERK1/2、MEK3/6、p38MAPK表达及其mRNA转录水平上调（P<0.01），Raf-1、FoxO3a、p-FoxO3a及MnSOD表达及其mRNA转录水平下调（P<0.01）。与模型组相比，各给药组大鼠术侧肾组织结构可见不同程度改善、纤维化面积可见不同程度减少；血清BUN、Cr、MDA、IL-6、TNF-α水平下降，SOD及GSH-px水平升高，SQXZD高剂量组及氯沙坦组差异具有统计学意义（P<0.05），SQXZD中剂量组差异具有统计学意义（P<0.01）；术侧肾组织α-SMA、Col-Ⅰ、NAKED2、Rap1、B-raf、MEK、ERK1/2、p-ERK1/2、MEK3/6、p38MAPK表达及其mRNA转录水平下调，Raf-1、FoxO3a、p-FoxO3a及MnSOD表达及其mRNA转录水平上调，SQXZD低、高剂量组及氯沙坦组差异具有统计学意义（P<0.05），SQXZD中剂量组差异具有统计学意义（P<0.01）。结论 SQXZD可改善肾功能、延缓肾纤维化，其机制可能是调控Rap1/MAPK/FoxO3a信号通路以改善氧化应激及炎症状态。

关键词: 参芪泄浊饮, 肾纤维化, 氧化应激, 炎症因子, Rap1/MAPK/FoxO3a信号通路

Abstract:

Objective To explore the mechanism of Shenqi Xiezhuo Decoction (SQXZD) for improving renal fibrosis (RF) in rats. Methods The chemical components of SQXZD were identified using UPLC-Q Exactive/MS, and component-disease target network and enrichment analyses were conducted to screen the key pathways and targets. In the animal experiment, 49 male SD rats were randomized equally into blank control group, sham operation group, unilateral ureteral obstruction-induced RF model group, losartan treatment (daily dose 4.6 mg/kg) group, and low-, medium-, and high-dose SQXZD (9.7, 19.4, and 38.8 g/kg, respectively) treatment groups. After 14 days' treatment, renal pathologies and collagen deposition of the rats were examined with HE and Masson staining, and serum levels of BUN, Cr, SOD, MDA, GSH-px, IL-6, and TNF-α were detected. Western blotting and qRT-PCR were used to detect renal protein and mRNA expressions of α‑SMA, Col-I, NAKED2, Rap1, B-raf, Raf-1, MEK3/6, p38MAPK, MEK, ERK1/2, p-ERK1/2, FoxO3a, p-FoxO3a, and MnSOD. Results A total of 263 chemical components were identified in SQXZD. Network pharmacology revealed 170 intersecting targets between the components and RF enriched in the MAPK, Rap1, and FoxO pathways. The rat models of RF showed abnormal renal structural changes, increased fibrosis area, elevated serum BUN, Cr, MDA, IL-6, and TNF-α levels, reduced SOD and GSH-px levels, upregulated renal expressions of α‑SMA, Col-I, NAKED2, Rap1, B-raf, MEK, ERK1/2, p-ERK1/2, MEK3/6, and p38MAPK, and downregulated Raf-1, FoxO3a, p-FoxO3a, and MnSOD expressions. Treatment with losartan and SQXZD (especially at the medium dose) obviously lessened renal pathologies, improved renal functions, alleviated oxidative stress and inflammation, and ameliorated abnormal changes in the Rap1/MAPK/FoxO3a signaling pathway in the rat models. Conclusion SQXZD alleviates RF and improves renal function in rats possibly by ameliorating renal oxidative stress and inflammation via regulating the Rap1/MAPK/FoxO3a signaling pathway.

Key words: Shenqi Xiezhuo Decoction, renal fibrosis, oxidative stress, inflammatory factors, Rap1/MAPK/FoxO3a signaling pathway

卢晓宇, 刘智慧, 刘烨, 庞天霄, 卞蓉, 郭玲, 何学红. 参芪泄浊饮通过调控Rap1/MAPK/FoxO3a信号通路改善氧化应激及炎症反应延缓大鼠肾纤维化[J]. 南方医科大学学报, 2025, 45(12): 2585-2597.

Xiaoyu LU, Zhihui LIU, Ye LIU, Tianxiao PANG, Rong BIAN, Ling GUO, Xuehong HE. Shenqi Xiezhuo Decoction alleviates renal fibrosis in rats by ameliorating oxidative stress and inflammation through the Rap1/MAPK/FoxO3a signaling pathway[J]. Journal of Southern Medical University, 2025, 45(12): 2585-2597.

图/表 17

表1 色谱梯度

Tab.1 Chromatographic gradient

Time (min)	Aqueous phase proportion(%)	Organic phase proportion(%)
1	98	2
5	80	20
10	50	50
15	20	80
20	5	95
27	5	95
28	98	2
30	98	2

表2 引物序列

Tab.2 Primer sequences

Gene	Primer sequences (5'-3')	Fragment length (bp)
α-SMA	F:ACCATCGGGAATGAACGCTT	191
α-SMA	R:CTGTCAGCAATGCCTGGGTA	191
Col1a1	F:CGTGGAAACCTGATGTATGCTTG	169
Col1a1	R:CCTATGACTTCTGCGTCTGGTGA	169
NAKED2	F:CGCCTCTGTCAATCATTCCTC	205
NAKED2	R:ATCTGTGTTGGGCTTCCTGCTATA	205
Rap1	F:GGATTGAAGGCACCAACCAT	144
Rap1	R:AGTAATTGAAGTGCTCCTTGCCG	144
Raf-1	F:GATGCTGTCTACTCGGATTGGC	116
Raf-1	R:GAAGTTGCTCTGGAGTTGGGTC	116
B-raf	F:CGCAAGATGTGGTGTAACGG	201
B-raf	R:AAGTTGTGGGTTGTCAGAGGAA	201
MEK	F:CGTGATGTCAAACCCTCCAAC	135
MEK	R:AGGAGCCATATAGGCAGCACAG	135
MEK3	F:TGAAGATGTGCGACTTTGGC	141
MEK3	R:CATCAGACTTGACGTTGTAGCCC	141
p38MAPK	F:ACCACGACCCTGATGATGAGC	94
p38MAPK	R:TAGGTCAGGCTCTTCCATTCGT	94
ERK	F:GAGACATCCTCAGAGCACCCA	216
ERK	R:TGTTGATAAGCAGATTGGAGGG	216
Foxo3a	F:AACAGTACCGTGTTCGGACC	119
Foxo3a	R:AGTGTCTGGTTGCCGTAGTG	119
MnSOD	F:TCTGGACAAACCTGAGCCCTAA	133
MnSOD	R:GAACCTTGGACTCCCACAGACA	133
GAPDH	F:CTGGAGAAACCTGCCAAGTATG	138
GAPDH	R:GGTGGAAGAATGGGAGTTGCT	138

图1 参芪泄浊饮药液提取总离子流图

Fig.1 Total ion chromatogram of Shenqi Xiezhuo Decoction (SQXZD) extract (Top: positive ion mode; Bottom: negative ion mode).

图2 参芪泄浊饮延缓肾纤维化的作用靶点Venn图

Fig.2 Venn diagram of the targets of SQXZD for delaying RF.

图3 "成分-靶点-疾病"网络图

Fig.3 "Component-Target-Disease" network diagram. Diamonds represent active components, and rectangles represent disease targets with a total of 1475 nodes and 11 241 edges.

图4 参芪泄浊饮延缓肾纤维化靶点的PPI网络图

Fig.4 PPI network diagram of the targets of SQXZD for delaying RF. Node color intensity corresponds to the Degree value, and darker colors indicate higher Degree values (169 nodes and 3682 edges).

图5 参芪泄浊饮延缓肾纤维化的GO功能富集分析

Fig.5 GO functional enrichment analysis of SQXZD in delaying RF. BP: Biological process; CC: Cellular component; MF: Molecular function.

图6 参芪泄浊饮延缓肾纤维化的KEGG通路富集分析

Fig.6 KEGG pathway enrichment analysis of SQXZD in delaying RF.

表3 参芪泄浊饮对UUO大鼠血清BUN、Cr的影响

Tab.3 Effects of SQXZD on serum BUN and Cr levels in rats with unilateral ureteral obstruction (UUO) (Mean±SD, n=5)

Group	BUN (mmol/L)	Cr (μmol/L)
Control	4.94±0.29	47.48±2.62
Sham	7.18±0.32	55.48±1.10
Model	28.08±2.35**	196.11±12.88**
Losartan	18.97±1.01^#	166.99±4.07^#
SQXZD low-dose	23.49±1.09	178.97±6.42
SQXZD medium-dose	16.79±0.55^▲	149.92±2.57^▲
SQXZD high-dose	19.03±1.01^#	171.32±3.68^#

图7 各组大鼠术侧肾脏HE染色

Fig.7 HE staining of the surgical-side kidney in each group of the rats (Original magnification: ×400).

图8 各组大鼠术侧肾脏Masson染色

Fig.8 Masson staining of the surgical-side kidney in each group of rats (×400).

表4 参芪泄浊饮对UUO大鼠血清SOD、MDA、GSH-px的影响

Tab.4 Effects of SQXZD on serum SOD， MDA and GSH-px levels in UUO rats (Mean±SD, n=5)

Group	SOD (U/mL)	MDA (μmol/L)	GSH-px (U/mL)
Control	325.42±6.59	2.03±0.14	2582.35±54.22
Sham	257.27±16.71	2.36±0.05	2238.14±105.60
Model	87.01±2.08**	8.92±0.94**	668.21±6.81**
Losartan	212.38±5.19^#	4.26±0.38^#	2048.18±45.04^#
SQXZD low-dose	183.70±5.04^#	7.50±0.52	1516.04±66.02^#
SQXZD medium-dose	270.46±5.87^▲	2.90±0.11^▲	2218.58±51.31^▲
SQXZD high-dose	209.35±5.60^#	5.42±0.20^#	1684.99±52.96^#

表5 参芪泄浊饮对UUO大鼠血清IL-6、TNF-α的影响

Tab.5 Effects of SQXZD on serum IL-6 and TNF‑α levels in UUO rats (Mean±SD, n=5)

Group	IL-6	TNF-α
Control	0.159±0.001	0.038±0.0003
Sham	0.177±0.005	0.040±0.0004
Model	0.309±0.010**	0.056±0.0011**
Losartan	0.243±0.004^#	0.051±0.0004^#
SQXZD low-dose	0.273±0.006	0.053±0.0006
SQXZD medium-dose	0.228±0.002^▲	0.049±0.0003^▲
SQXZD high-dose	0.252±0.005^#	0.051±0.0005^#

图9 参芪泄浊饮对UUO大鼠术侧肾组织α-SMA、Col-Ⅰ、NAKED2表达的影响

Fig.9 Effects of SQXZD on expressions of α-SMA, Col-I and NAKED2 in the surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

图10 参芪泄浊饮对UUO大鼠术侧肾组织α-SMA、Col1a1、NAKED2 mRNA转录水平的影响

Fig.10 Effects of SQXZD on mRNA transcription levels of α-SMA, Col1a1 and NAKED2 in the surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

图11 参芪泄浊饮对UUO大鼠术侧肾组织Rap1、B-raf、Raf-1、MEK3/6、p38MAPK、MEK、ERK1/2、p-ERK1/2、FoxO3a、p-FoxO3a及MnSOD表达的影响

Fig.11 Effects of SQXZD on expressions of Rap1, B-raf, Raf-1, MEK3/6, p38MAPK, MEK, ERK1/2, p-ERK1/2, FoxO3a, p-FoxO3a and MnSOD in surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

图12 参芪泄浊饮对UUO大鼠术侧肾组织Rap1、B-raf、Raf-1、MEK3、p38MAPK、MEK、ERK、FoxO3a及MnSOD mRNA转录水平的影响

Fig.12 Effects of SQXZD on mRNA transcription levels of Rap1, B-raf, Raf-1, MEK3, p38MAPK, MEK, ERK, FoxO3a and MnSOD in surgical-side kidneys of UUO rats.**P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

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