姜黄素对糖尿病肾脏病大鼠肾组织坏死性凋亡的影响

doi:10.3877/cma.j.issn.2095-3216.2026.02.004

目的

探讨姜黄素对糖尿病肾脏病大鼠肾组织细胞坏死性凋亡的影响。

方法

将成年雄性SD大鼠随机分为对照组、糖尿病肾脏病模型组(一次性腹腔注射链脲佐菌素55 mg/kg)、糖尿病肾脏病模型＋姜黄素组[造模后予以姜黄素混悬液200 mg/(kg·d)灌胃]、糖尿病肾脏病模型＋羧甲基纤维素钠组(造模后每天予以等体积5%羧甲基纤维素钠灌胃)，每组各12只。监测大鼠一般状态变化，分别于第8、12周采集尿液和血液，检测24 h尿蛋白以及血糖、血清肌酐和血尿素氮，并取双侧肾脏行病理组织学观察，以免疫组化、Western印迹及qRT-PCR法检测肾组织肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)、受体相互作用蛋白1(receptor-interacting protein 1, RIP1)、RIP3、混合谱系激酶结构域样蛋白(mixed lineage kinase domain-like protein, MLKL)、转化生长因子-β(transforming growth factor-β，TGF-β)和白细胞介素-18(interleukin-18, IL-18)蛋白及基因表达。

结果

与对照组相比，糖尿病肾脏病模型组和糖尿病肾脏病模型＋羧甲基纤维素钠组大鼠的一般状态差，肾小球内结构紊乱、肾小管肿胀，血和尿的生化指标均增高(P均<0.01)，肾组织的TNF-α、RIP1、RIP3、MLKL、TGF-β和IL-18表达均上调(P均<0.01)。与糖尿病肾脏病模型＋羧甲基纤维素钠组相比较，糖尿病肾脏病模型＋姜黄素组大鼠的一般状况明显好转，肾小球及肾小管病变减轻，血和尿的生化指标均下降(P均<0.01)，肾组织的TNF-α、RIP1、RIP3、MLKL、TGF-β和IL-18表达亦下调(P均<0.01)。

结论

姜黄素可能通过抑制糖尿病肾脏病大鼠肾组织的TNF-α表达，部分地抑制坏死性凋亡途径激活和炎症因子释放，从而减轻肾组织的炎症和损伤。

关键词: 糖尿病肾脏病, 姜黄素, 肿瘤坏死因子-α, 坏死性凋亡途径, 炎症, 减轻

Objective

To investigate the effect of curcumin on renal necroptosis in diabetic kidney disease rats.

Methods

Adult male Sprague-Dawley (SD) rats were randomly divided into four groups (n=12 per group): a control group, a diabetic kidney disease (DKD) model group (intraperitoneal injection of a single dose of streptozotocin at 55 mg/kg), a DKD model+ curcumin group [daily intraperitoneal injection of curcumin suspension at 200 mg/(kg·d) via intragastric gavage after modeling], and a DKD model + carboxymethyl cellulose sodium (CMC-Na) group (daily intraperitoneal injection of an equal volume of 5% CMC-Na via intragastric gavage after modeling). General conditions of the rats were monitored throughout the study. Urine and blood samples were collected at weeks 8 and 12 to measure 24-h urinary protein, blood glucose, serum creatinine, and blood urea nitrogen (BUN). And bilateral kidneys were harvested for histopathological examination. Furthermore, the protein and mRNA expression levels of tumor necrosis factor-α (TNF-α), receptor-interacting protein 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL), transforming growth factor-β (TGF-β), and interleukin-18 (IL-18) in renal tissues were detected using immunohistochemistry, Western blotting, and qRT-PCR, respectively.

Results

Compared with the control group, rats in the DKD model group and the DKD model+ CMC-Na group exhibited poor general conditions, along with disordered glomerular structure and tubular swelling. Both blood and urinary biochemical indices were significantly elevated (all P<0.01). Furthermore, the expression levels of TNF-α, RIP1, RIP3, MLKL, TGF-β, and IL-18 in renal tissues were also significantly upregulated (P<0.01). Compared with the DKD model+ CMC-Na group, rats in the DKD model + curcumin group showed significant improvement in general conditions and alleviation of glomerular and tubular lesions. Both blood and urinary biochemical indices were significantly decreased (P<0.01). Moreover, the expression levels of TNF-α, RIP1, RIP3, MLKL, TGF-β, and IL-18 in renal tissues were also downregulated (P<0.01).

Conclusion

Curcumin may attenuate renal inflammation and injury in DKD rats by inhibiting TNF-α expression, thereby partially suppressing the activation of the necroptosis pathway and the release of inflammatory cytokines.

Key words: Diabetic kidney disease, Curcumin, Tumor necrosis factor-α, Necroptosis pathway, Inflammation, Attenuation

表1 qRT-PCR引物序列

基因	正向引物(5′-3′)	反向引物(5′-3′)
β-actin	ATGACGATATCGCTGCGCT	TACCCACCATCACACCCTGG
TNF-α	ATCGGTCCCAACAAGGAGGA	GCTTGGTGGTTTGCTACGA
RIP1	GGAGATCCAGAGTCGCCAG	CCTCCCGCTCTTCATGGAC
RIP3	TGTCTTCTGTCAAGTTATGGCTCA	CACCATAGCCTTCACCTCCC
MLKL	ACTGTGAACTCGGAACCCTG	TCCCGAGTGGTGTAACCTGTA
TGF-β	CTGCTGACCCCCACTGATAC	AGCCCTGTATTCCGTCTCCT
IL-18	TGCCATACCAGAAGAAGGCT	TGGGATTCGTTGGCTGTTCG

表1 qRT-PCR引物序列

基因	正向引物(5′-3′)	反向引物(5′-3′)
β-actin	ATGACGATATCGCTGCGCT	TACCCACCATCACACCCTGG
TNF-α	ATCGGTCCCAACAAGGAGGA	GCTTGGTGGTTTGCTACGA
RIP1	GGAGATCCAGAGTCGCCAG	CCTCCCGCTCTTCATGGAC
RIP3	TGTCTTCTGTCAAGTTATGGCTCA	CACCATAGCCTTCACCTCCC
MLKL	ACTGTGAACTCGGAACCCTG	TCCCGAGTGGTGTAACCTGTA
TGF-β	CTGCTGACCCCCACTGATAC	AGCCCTGTATTCCGTCTCCT
IL-18	TGCCATACCAGAAGAAGGCT	TGGGATTCGTTGGCTGTTCG

图1 各组大鼠血糖、24 h尿蛋白定量及肾功能指标比较注：A：两组不同时间点血糖水平比较；B：两组不同时间点24 h尿蛋白水平比较；C：两组不同时间点血清尿素水平比较；D：两组不同时间点血清肌酐水平比较；Control：对照组；DKD：糖尿病肾脏病模型组；DKD＋Cur：糖尿病肾脏病模型＋姜黄素组；DKD＋CMC：糖尿病肾脏病模型＋羧甲基纤维素钠组；与对照组比较，^aP<0.01；与糖尿病肾脏病模型＋姜黄素组比较，^bP<0.01；与糖尿病肾脏病模型组比较，^cP>0.05

图2 各组大鼠肾组织苏木精-伊红染色结果比较注：A：各组大鼠肾组织苏木精-伊红染色(×400)；B：各组大鼠肾组织苏木精-伊红染色病理损伤评分；与对照组比较，^aP<0.01；与糖尿病肾脏病模型＋姜黄素组比较，^bP<0.01；与糖尿病肾脏病模型组比较，^cP>0.05；Control：对照组；DKD：糖尿病肾脏病模型组；DKD＋Cur：糖尿病肾脏病模型＋姜黄素组；DKD＋CMC：糖尿病肾脏病模型＋羧甲基纤维素钠组

图3 各组大鼠肾组织过碘酸-雪夫染色结果比较注：A：各组大鼠肾组织过碘酸-雪夫染色(×400)；B：各组大鼠肾组织过碘酸-雪夫染色病理损伤评分；与对照组比较，^aP<0.01；与糖尿病肾脏病模型＋姜黄素组比较，^bP<0.01；与糖尿病肾脏病模型组组比较，^cP>0.05；Control：对照组；DKD：糖尿病肾脏病模型组；DKD＋Cur：糖尿病肾脏病模型＋姜黄素组；DKD＋CMC：糖尿病肾脏病模型＋羧甲基纤维素钠组

图4 免疫组化法检测各组大鼠肾组织中坏死性凋亡标志物及相关炎症因子表达注：A：各组大鼠肾组织肿瘤坏死因子-α免疫组化图(×400)；B：各组大鼠肾组织受体相互作用蛋白1免疫组化图(×400)；C：各组大鼠肾组织受体相互作用蛋白3免疫组化图(×400)；D：各组大鼠肾组织混合谱系激酶结构域样蛋白免疫组化图(×400)；E：各组大鼠肾组织转化生长因子-β免疫组化图(×400)；F：各组大鼠肾组织白细胞介素-18免疫组化图(×400)；Control：对照组；DKD：糖尿病肾脏病模型组；DKD＋Cur：糖尿病肾脏病模型＋姜黄素组；DKD＋CMC：糖尿病肾脏病模型＋羧甲基纤维素钠组

表2 肾组织中坏死性凋亡标志物及相关炎症因子的免疫组化阳性染色比(%，

±s)

组别	TNF-α		RIP1		RIP3
组别	8周	12周	8周	12周	8周	12周
Control	0.22±0.04	0.21±0.04	0.18±0.04	0.14±0.04	0.43±0.13	0.48±0.11
DKD	1.79±0.18^ab	1.85±0.08^ab	1.72±0.13^ab	1.88±0.11^ab	1.70±0.16^ab	1.84±0.18^ab
DKD＋CMC	1.73±0.17^abc	1.80±0.16^abc	1.66±0.13^abc	1.82±0.16^abc	1.78±0.22^abc	1.97±0.19^abc
DKD＋Cur	0.97±0.10	0.99±0.13	0.99±0.11	1.82±0.17	1.02±0.18	1.08±0.24
组别	MLKL		TGF-β		IL-18
组别	8周	12周	8周	12周	8周	12周
Control	0.31±0.09	0.32±0.10	0.37±0.12	0.47±0.06	0.20±0.07	0.20±0.13
DKD	1.70±0.12^ab	1.65±0.20^ab	1.97±0.15^ab	1.80±0.23^ab	1.63±0.10^ab	1.83±0.17^ab
DKD＋CMC	1.78±0.23^abc	1.60±0.21^abc	1.88±0.20^abc	1.96±0.13^abc	1.66±0.99^abc	1.79±0.11^abc
DKD＋Cur	0.99±0.15	0.93±0.14	1.27±0.18	1.13±0.20	0.94±0.17	1.02±0.14

表2 肾组织中坏死性凋亡标志物及相关炎症因子的免疫组化阳性染色比(%，

±s)

组别	TNF-α		RIP1		RIP3
组别	8周	12周	8周	12周	8周	12周
Control	0.22±0.04	0.21±0.04	0.18±0.04	0.14±0.04	0.43±0.13	0.48±0.11
DKD	1.79±0.18^ab	1.85±0.08^ab	1.72±0.13^ab	1.88±0.11^ab	1.70±0.16^ab	1.84±0.18^ab
DKD＋CMC	1.73±0.17^abc	1.80±0.16^abc	1.66±0.13^abc	1.82±0.16^abc	1.78±0.22^abc	1.97±0.19^abc
DKD＋Cur	0.97±0.10	0.99±0.13	0.99±0.11	1.82±0.17	1.02±0.18	1.08±0.24
组别	MLKL		TGF-β		IL-18
组别	8周	12周	8周	12周	8周	12周
Control	0.31±0.09	0.32±0.10	0.37±0.12	0.47±0.06	0.20±0.07	0.20±0.13
DKD	1.70±0.12^ab	1.65±0.20^ab	1.97±0.15^ab	1.80±0.23^ab	1.63±0.10^ab	1.83±0.17^ab
DKD＋CMC	1.78±0.23^abc	1.60±0.21^abc	1.88±0.20^abc	1.96±0.13^abc	1.66±0.99^abc	1.79±0.11^abc
DKD＋Cur	0.99±0.15	0.93±0.14	1.27±0.18	1.13±0.20	0.94±0.17	1.02±0.14

图5 Western印迹和qRT-PCR法检测各组大鼠肾组织中坏死性凋亡标志物及相关炎症因子的蛋白和基因表达注：A：8周时DKD大鼠肾组织中的蛋白表达；B：12周时DKD大鼠肾组织中的蛋白表达；C：DKD大鼠肾组织中TNF-α的核酸表达；D：DKD大鼠肾组织中RIP1的核酸表达；E：DKD大鼠肾组织中RIP3的核酸表达；F：DKD大鼠肾组织中MLKL的核酸表达；G：DKD大鼠肾组织中TGF-β的核酸表达；H：DKD大鼠肾组织中IL-18的核酸表达；与Control组比较，^aP<0.01；与DKD＋Cur组比较，^bP<0.01；与DKD组比较，^cP>0.05；Control：对照组；DKD：糖尿病肾脏病模型组；DKD＋Cur：糖尿病肾脏病模型＋姜黄素组；DKD＋CMC：糖尿病肾脏病模型＋羧甲基纤维素钠组；TNF-α：tumor necrosis factor-α，肿瘤坏死因子-α；RIP：receptor-interacting protein，受体相互作用蛋白；MLKL：mixed lineage kinase domain-like protein，混合谱系激酶结构域样蛋白；TGF-β：transforming growth factor-β，转化生长因子-β；IL-18：interleukin-18，白细胞介素-18

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Effect of curcumin on renal necroptosis in diabetic kidney disease rats

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Effect of curcumin on renal necroptosis in diabetic kidney disease rats