小儿肾病综合征ox-LDL脂质肾损伤及肾康灵干预的机制研究
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摘要
目的：
体外实验以氧化低密度脂蛋白(oxidized low density lipoprotein, ox-LDL)诱导系膜细胞(mesangial cells,MCs)增殖,观察其分泌CXCL16、CD36、解聚素与金属蛋白酶10(a disintegrin and metalloprotease10, ADAM10)、ADAM17的水平以及丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路相关蛋白的磷酸化水平；体内实验以阿霉素肾病(adriamycin nephropathy,AN)大鼠为研究对象,观察其肾组织的CXCL16、CD36、 ADAM10、ADAM17水平及MAPK信号通路相关蛋白的活性,阐明脂质对肾损伤的作用机制。同时应用益肾活血中药肾康灵进行干预,观察治疗前后CXCL16、CD36、ADAM10、 ADAM17及MAPK信号通路相关蛋白的变化,从分子生物学及基因学水平进一步阐明益肾活血中药肾康灵干预PNS的作用机制,为提高小儿PNS的临床疗效和益肾活血法的临床应用奠定基础。
方法：
(1)基础研究：体外实验将MCs按随机数表法分为7组：①正常对照组；②ox-LDL组：③ox-LDL+CXCR6组：④ox-LDL+肾康灵低浓度组；⑤ox-LDL+1肾康灵高浓度组；⑥ox-LDL+阿托伐他汀低浓度组；⑦ox-LDL+阿托伐他汀高浓度组。采用MTT比色法测定MCs的增殖比率；分别采用ELISA法检测MCs的CXCL16、CD36、IFN-γ、IL-6、TNF-α含量,Real Time-PCR、Western blot法检测MCs的CXCL16、CD36、ADAM10、ADAM17的基因水平及其蛋白含量。采用Western Blot方法检测MAPK通路相关蛋白(p38、JNK、 ERK)及核因子-κB (nuclear factor kappa B,NF-κB)的磷酸化水平。体内实验将大鼠按体质量分层随机法分为5组：①正常组；②AN病模组；③肾康灵(低浓度)+西药组15只；④肾康灵(高浓度)+西药组；⑤西药组。各组连续灌胃22d。灌胃结束后,分别采用Real Time-PCR、Western blot法检测大鼠肾组织的CXCL16、CD36、ADAM10、ADAM17的基因水平及其蛋白含量,并检测尿蛋白定量及血白蛋白(albumin,ALB)、胆固醇(cholesterol,CH)水平,通过HE染色,电镜观察并分析肾组织病理形态学。
(2)临床研究：PNS患儿采用随机数表法分为肾康灵+西药组和西药组,同时在体检中心抽取健康体检儿童为健康对照组。采用ELISA法检测PNS患儿治疗前后血清CXCL16、 ADAM10、ADAM17的分泌变化,同时检测血ALB、CH、24小时尿蛋白定量等以进行疗效评价。
结果：
(1)基础研究：体外实验表明利用ox-LDL诱导大鼠系膜细胞增殖后,其表面CXCL16、 CD36、IFN-γ、IL6、TNF-α的表达显著升高(P<0.01),加入CXCR6受体后,其表达水平进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低上述指标(P<0.01); ox-LDL诱导大鼠系膜细胞增殖后,CXCL16、CD36、ADAM10、ADAM17的基因水平和蛋白含量显著升高(P<0.01),加入CXCR6受体后,其基因水平和蛋白含量进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低上述指标(P<0.01或P<0.05); ox-LDL诱导大鼠系膜细胞增殖后,MCs表面的p38、ERK1/2、SAPK/JNK、NF-κ Bp65的磷酸化水平显著升高(P<0.01),加入CXCR6受体后,其磷酸化水平进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低ERK1/2、SAPK/JNK、NF-κ B p65的磷酸化水平(P<0.01)。体内实验表明AN大鼠的尿蛋白定量升高、血清ALB降低、CH升高、肾组织的CXCL16、CD36、 ADAM10、ADAM17的基因水平和蛋白含量升高,p38、ERK1/2、SAPK/JNK、NF-κ B p65的磷酸化水平升高(P<0.01),肾康灵+西药松组呈浓度依赖性降低CXCL16、CD36、 ADAM10、ADAM17的表达,降低p38、ERK1/2、SAPK/JNK、NF-κ Bp65的磷酸化水平(P<0.01)；肾康灵(高、低浓度)+西药组的CH水平与西药组相比显著降低(P<0.01或P<0.05)。
(2)临床研究表明,PNS患儿的尿蛋白定量升高、血清ALB降低、CH升高、CXCL16、 ADAM10、ADAM17的含量升高(P<0.01),肾康灵+西药治疗组在降低尿蛋白定量、CH及血清CXCL16、ADAM10、ADAM17的含量方面明显优于西药组(P<0.01或P<0.05)。
结论：
(1)ox-LDL可促使系膜细胞释放CXCL16、CD36、ADAM10、ADAM17等炎症介质,CXCR6可介导这一途径。ox-LDL激活了MAPK信号转导通路,使p38、ERK1/2、 SAPK/JNK的磷酸化水平升高,激活了NF-κ Bp65的活性,CXCR6-CXCL16介导MAPK信号途径。
(2)益肾活血中药肾康灵通过降低CXCL16、CD36、ADAM10、ADAM17等炎症介质的释放及抑制MAPK信号转导通路的激活,从而抑制系膜细胞的增殖,降低尿蛋白、CH水平,有效地改善AN大鼠的病理损伤和PNS患儿的临床症状。
Purpose:
In vitro, oxidized low density lipoprotein(ox-LDL) induced MCs proliferation, observe CXCL16, CD36, ADAM10, ADAM17levels and mitogen-activated protein kinase (MAPK) signaling pathway protein phosphorylation levels; In vivo, rats with adriamycin nephropathy (AN) as the research object, observe the CXCL16,CD36,disintegrin and metalloproteinase10, the ADAM17level and MAPK signaling pathway related proteins in renal tissue to clarify the mechanism of action of lipids on renal injury. Before and after intervention of Yishenhuoxue Chinese medicine Shenkangling,through observing the change of CXCL16,CD36,ADAM10, ADAM17and MAPK signal transduction pathway,and to clarify the mechanism of action of the intervention Yishenhuoxue, from the level of molecular biology and genetics, to improve the clinical application of the PNS clinical efficacy and Yishenhuoxue law, providing the basis for the clinical application of Yishenhuoxue.
Methods:
(1) basic research:in vitro, MCs were randomly divided into seven groups:①normal control group;②ox-LDL group;③ox-LDL+CXCR6group;④ox-LDL+low Shenkangling concentration group;⑤ox-LDL+high Shenkangling concentration group;⑥ox-LDL+low atorvastatin concentration group;⑦ox-LDL+high atorvastatin concentration group. MCs proliferation ratio was determined by MTT assay; CXCL16, CD36, IFN-γ, IL6, TNF-α content detected by ELISA, CXCL16, CD36, ADAM10level of ADAM17gene and its protein content assayed by Real Time-PCR, Western blot. MAPK pathway related protein (p38, JNK, ERK) and NF-κB phosphorylation levels detected by Western Blot.
In Vivo, rats were divided into five groups according to body mass stratified random method:①normal group;②AN disease module;③low Shenkangling concentration group+prednisone;④high Shenkangling concentration group+prednisone;⑤prednisone group. The each group intragastrically continuous22days. After gavage, respectively, using Real Time-PCR, Western blot to assay CXCL16, CD36, ADAM10and ADAM17gene level and its protein content of rat kidney tissue, and detect urine protein and serum albumin, the level of cholesterol, analysis of renal Pathomorphology by HE staining and electron microscopy.
(2) clinical research:PNS children randomly divided into the Shenkangling+western medicine group and the western medicine group, healthy children as normal control group selected in the examination center. Serum CXCL16, ADAM10and AD AM17Detected by ELISA in children with PNS before treatment and after-treatment, at the same time,serum ALB, CH,24-hour urinary protein excretion efficacy evaluation.
Results:
(1) basic research:in vitro, ox-LDL-induced proliferation of rat mesangial cells, CXCL16, CD36, IFN-γ, IL6, TNF-α expression was significantly increased (P<0.01), after adding CXCR6receptor, its expression level was further increased (P<0.01). The serum containing Shenkangling reducing the above indicators dose-dependently (P<0.01); ox-LDL-induced proliferation of rat mesangial cells, CXCL16, CD36, ADAM10and ADAM17gene level and protein content were significantly increased (P<0.01), after adding CXCR6receptor, gene level and protein content were further increased (P<0.01), Shenkangling containing serum reduced these indicators dose-dependently (P<0.01or P<0.05); ox-LDL-induced proliferation of rat mesangial cells, phosphorylation levels of NF-κBp65, p38, ERK1/2, SAPK/JNK were significantly increased (P <0.01), after adding CXCR6receptor phosphorylation levels further increased (P<0.01), The Shenkangling containing serum dose-dependently reduced ERK1/2, SAPK/JNK, NF-κB p65phosphorylation level (P<0.01).
In vivo, urinary protein excretion increased in AN rats, serum ALB lower, CH increased, CXCL16, CD36, ADAM10and ADAM17gene level and protein content increased in renal tissue, p38, ERK1/2, SAPK/JNK, NF-κB p65phosphorylation levels increased (P<0.01), Shenkangling+prednisone group showed a concentration-dependent reduction in CXCL16, CD36, ADAM10, ADAM17expression, reduced p38, ERK1/2, SAPK/JNK NF-κBp65in phosphorylation level (P<0.01); CH level significantly reduced in Shenkangling (high, low concentration)+the prednisone group compared with the prednisone group (P<0.01or P<0.05).
(2) clinical study:elevated PNS children with urinary protein excretion, serum ALB reduce, CH increased CXCL16, ADAM10, ADAM17content increased (P<0.01), Shenkangling+western medicine group and western medicine group compared to reduce urinary protein quantitation, CH and serum CXCL16, ADAM10, ADAM17's content more significant (P<0.01or P<0.05).
Conclusion:
(1) ox-LDL may promote the release of inflammatory mediators such as CXCL16, CD36, ADAM10, ADAM17in mesangial cells, CXCR.6may mediated this path. ox-LDL activates the MAPK signal transduction pathway, the p38, ERK1/2, SAPK/JNK phosphorylation levels increased, activated NF-κBp65,CXCR6-CXCL16mediated MAPK signaling pathways.
(2) Yi shen huo xue Shenkangling by reducing the release of inflammatory mediators such as CXCL16, CD36, ADAM10, ADAM17and inhibit the activation of the MAPK signal transduction pathway, thereby inhibiting the proliferation of mesangial cells, reducing proteinuria, CH, improve AN rats pathological damage, effectively improve the clinical symptoms of children with PNS.
体外实验以氧化低密度脂蛋白(oxidized low density lipoprotein, ox-LDL)诱导系膜细胞(mesangial cells,MCs)增殖,观察其分泌CXCL16、CD36、解聚素与金属蛋白酶10(a disintegrin and metalloprotease10, ADAM10)、ADAM17的水平以及丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路相关蛋白的磷酸化水平；体内实验以阿霉素肾病(adriamycin nephropathy,AN)大鼠为研究对象,观察其肾组织的CXCL16、CD36、 ADAM10、ADAM17水平及MAPK信号通路相关蛋白的活性,阐明脂质对肾损伤的作用机制。同时应用益肾活血中药肾康灵进行干预,观察治疗前后CXCL16、CD36、ADAM10、 ADAM17及MAPK信号通路相关蛋白的变化,从分子生物学及基因学水平进一步阐明益肾活血中药肾康灵干预PNS的作用机制,为提高小儿PNS的临床疗效和益肾活血法的临床应用奠定基础。
方法：
(1)基础研究：体外实验将MCs按随机数表法分为7组：①正常对照组；②ox-LDL组：③ox-LDL+CXCR6组：④ox-LDL+肾康灵低浓度组；⑤ox-LDL+1肾康灵高浓度组；⑥ox-LDL+阿托伐他汀低浓度组；⑦ox-LDL+阿托伐他汀高浓度组。采用MTT比色法测定MCs的增殖比率；分别采用ELISA法检测MCs的CXCL16、CD36、IFN-γ、IL-6、TNF-α含量,Real Time-PCR、Western blot法检测MCs的CXCL16、CD36、ADAM10、ADAM17的基因水平及其蛋白含量。采用Western Blot方法检测MAPK通路相关蛋白(p38、JNK、 ERK)及核因子-κB (nuclear factor kappa B,NF-κB)的磷酸化水平。体内实验将大鼠按体质量分层随机法分为5组：①正常组；②AN病模组；③肾康灵(低浓度)+西药组15只；④肾康灵(高浓度)+西药组；⑤西药组。各组连续灌胃22d。灌胃结束后,分别采用Real Time-PCR、Western blot法检测大鼠肾组织的CXCL16、CD36、ADAM10、ADAM17的基因水平及其蛋白含量,并检测尿蛋白定量及血白蛋白(albumin,ALB)、胆固醇(cholesterol,CH)水平,通过HE染色,电镜观察并分析肾组织病理形态学。
(2)临床研究：PNS患儿采用随机数表法分为肾康灵+西药组和西药组,同时在体检中心抽取健康体检儿童为健康对照组。采用ELISA法检测PNS患儿治疗前后血清CXCL16、 ADAM10、ADAM17的分泌变化,同时检测血ALB、CH、24小时尿蛋白定量等以进行疗效评价。
结果：
(1)基础研究：体外实验表明利用ox-LDL诱导大鼠系膜细胞增殖后,其表面CXCL16、 CD36、IFN-γ、IL6、TNF-α的表达显著升高(P<0.01),加入CXCR6受体后,其表达水平进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低上述指标(P<0.01); ox-LDL诱导大鼠系膜细胞增殖后,CXCL16、CD36、ADAM10、ADAM17的基因水平和蛋白含量显著升高(P<0.01),加入CXCR6受体后,其基因水平和蛋白含量进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低上述指标(P<0.01或P<0.05); ox-LDL诱导大鼠系膜细胞增殖后,MCs表面的p38、ERK1/2、SAPK/JNK、NF-κ Bp65的磷酸化水平显著升高(P<0.01),加入CXCR6受体后,其磷酸化水平进一步升高(P<0.01),肾康灵含药血清组呈浓度依赖性降低ERK1/2、SAPK/JNK、NF-κ B p65的磷酸化水平(P<0.01)。体内实验表明AN大鼠的尿蛋白定量升高、血清ALB降低、CH升高、肾组织的CXCL16、CD36、 ADAM10、ADAM17的基因水平和蛋白含量升高,p38、ERK1/2、SAPK/JNK、NF-κ B p65的磷酸化水平升高(P<0.01),肾康灵+西药松组呈浓度依赖性降低CXCL16、CD36、 ADAM10、ADAM17的表达,降低p38、ERK1/2、SAPK/JNK、NF-κ Bp65的磷酸化水平(P<0.01)；肾康灵(高、低浓度)+西药组的CH水平与西药组相比显著降低(P<0.01或P<0.05)。
(2)临床研究表明,PNS患儿的尿蛋白定量升高、血清ALB降低、CH升高、CXCL16、 ADAM10、ADAM17的含量升高(P<0.01),肾康灵+西药治疗组在降低尿蛋白定量、CH及血清CXCL16、ADAM10、ADAM17的含量方面明显优于西药组(P<0.01或P<0.05)。
结论：
(1)ox-LDL可促使系膜细胞释放CXCL16、CD36、ADAM10、ADAM17等炎症介质,CXCR6可介导这一途径。ox-LDL激活了MAPK信号转导通路,使p38、ERK1/2、 SAPK/JNK的磷酸化水平升高,激活了NF-κ Bp65的活性,CXCR6-CXCL16介导MAPK信号途径。
(2)益肾活血中药肾康灵通过降低CXCL16、CD36、ADAM10、ADAM17等炎症介质的释放及抑制MAPK信号转导通路的激活,从而抑制系膜细胞的增殖,降低尿蛋白、CH水平,有效地改善AN大鼠的病理损伤和PNS患儿的临床症状。
Purpose:
In vitro, oxidized low density lipoprotein(ox-LDL) induced MCs proliferation, observe CXCL16, CD36, ADAM10, ADAM17levels and mitogen-activated protein kinase (MAPK) signaling pathway protein phosphorylation levels; In vivo, rats with adriamycin nephropathy (AN) as the research object, observe the CXCL16,CD36,disintegrin and metalloproteinase10, the ADAM17level and MAPK signaling pathway related proteins in renal tissue to clarify the mechanism of action of lipids on renal injury. Before and after intervention of Yishenhuoxue Chinese medicine Shenkangling,through observing the change of CXCL16,CD36,ADAM10, ADAM17and MAPK signal transduction pathway,and to clarify the mechanism of action of the intervention Yishenhuoxue, from the level of molecular biology and genetics, to improve the clinical application of the PNS clinical efficacy and Yishenhuoxue law, providing the basis for the clinical application of Yishenhuoxue.
Methods:
(1) basic research:in vitro, MCs were randomly divided into seven groups:①normal control group;②ox-LDL group;③ox-LDL+CXCR6group;④ox-LDL+low Shenkangling concentration group;⑤ox-LDL+high Shenkangling concentration group;⑥ox-LDL+low atorvastatin concentration group;⑦ox-LDL+high atorvastatin concentration group. MCs proliferation ratio was determined by MTT assay; CXCL16, CD36, IFN-γ, IL6, TNF-α content detected by ELISA, CXCL16, CD36, ADAM10level of ADAM17gene and its protein content assayed by Real Time-PCR, Western blot. MAPK pathway related protein (p38, JNK, ERK) and NF-κB phosphorylation levels detected by Western Blot.
In Vivo, rats were divided into five groups according to body mass stratified random method:①normal group;②AN disease module;③low Shenkangling concentration group+prednisone;④high Shenkangling concentration group+prednisone;⑤prednisone group. The each group intragastrically continuous22days. After gavage, respectively, using Real Time-PCR, Western blot to assay CXCL16, CD36, ADAM10and ADAM17gene level and its protein content of rat kidney tissue, and detect urine protein and serum albumin, the level of cholesterol, analysis of renal Pathomorphology by HE staining and electron microscopy.
(2) clinical research:PNS children randomly divided into the Shenkangling+western medicine group and the western medicine group, healthy children as normal control group selected in the examination center. Serum CXCL16, ADAM10and AD AM17Detected by ELISA in children with PNS before treatment and after-treatment, at the same time,serum ALB, CH,24-hour urinary protein excretion efficacy evaluation.
Results:
(1) basic research:in vitro, ox-LDL-induced proliferation of rat mesangial cells, CXCL16, CD36, IFN-γ, IL6, TNF-α expression was significantly increased (P<0.01), after adding CXCR6receptor, its expression level was further increased (P<0.01). The serum containing Shenkangling reducing the above indicators dose-dependently (P<0.01); ox-LDL-induced proliferation of rat mesangial cells, CXCL16, CD36, ADAM10and ADAM17gene level and protein content were significantly increased (P<0.01), after adding CXCR6receptor, gene level and protein content were further increased (P<0.01), Shenkangling containing serum reduced these indicators dose-dependently (P<0.01or P<0.05); ox-LDL-induced proliferation of rat mesangial cells, phosphorylation levels of NF-κBp65, p38, ERK1/2, SAPK/JNK were significantly increased (P <0.01), after adding CXCR6receptor phosphorylation levels further increased (P<0.01), The Shenkangling containing serum dose-dependently reduced ERK1/2, SAPK/JNK, NF-κB p65phosphorylation level (P<0.01).
In vivo, urinary protein excretion increased in AN rats, serum ALB lower, CH increased, CXCL16, CD36, ADAM10and ADAM17gene level and protein content increased in renal tissue, p38, ERK1/2, SAPK/JNK, NF-κB p65phosphorylation levels increased (P<0.01), Shenkangling+prednisone group showed a concentration-dependent reduction in CXCL16, CD36, ADAM10, ADAM17expression, reduced p38, ERK1/2, SAPK/JNK NF-κBp65in phosphorylation level (P<0.01); CH level significantly reduced in Shenkangling (high, low concentration)+the prednisone group compared with the prednisone group (P<0.01or P<0.05).
(2) clinical study:elevated PNS children with urinary protein excretion, serum ALB reduce, CH increased CXCL16, ADAM10, ADAM17content increased (P<0.01), Shenkangling+western medicine group and western medicine group compared to reduce urinary protein quantitation, CH and serum CXCL16, ADAM10, ADAM17's content more significant (P<0.01or P<0.05).
Conclusion:
(1) ox-LDL may promote the release of inflammatory mediators such as CXCL16, CD36, ADAM10, ADAM17in mesangial cells, CXCR.6may mediated this path. ox-LDL activates the MAPK signal transduction pathway, the p38, ERK1/2, SAPK/JNK phosphorylation levels increased, activated NF-κBp65,CXCR6-CXCL16mediated MAPK signaling pathways.
(2) Yi shen huo xue Shenkangling by reducing the release of inflammatory mediators such as CXCL16, CD36, ADAM10, ADAM17and inhibit the activation of the MAPK signal transduction pathway, thereby inhibiting the proliferation of mesangial cells, reducing proteinuria, CH, improve AN rats pathological damage, effectively improve the clinical symptoms of children with PNS.
引文
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