中华肾脏病杂志
中華腎髒病雜誌
중화신장병잡지
2008年
3期
168-173
,共6页
王芳%杨念生%罗明乾%李嵘%张黎黎%王双%张锐%余学清
王芳%楊唸生%囉明乾%李嶸%張黎黎%王雙%張銳%餘學清
왕방%양념생%라명건%리영%장려려%왕쌍%장예%여학청
输尿管梗阻%纤维化%巨噬细胞%信号传导%肾间质
輸尿管梗阻%纖維化%巨噬細胞%信號傳導%腎間質
수뇨관경조%섬유화%거서세포%신호전도%신간질
Ureteral obstruction%Fibrosis%Macrophages%Signal transduction%Renal interstitium
目的 探讨Janus蛋白酪氨酸激酶-信号转导子和转录激活子(JAK-STAT)通路在小鼠单侧输尿管梗阻(UUO)模型.肾间质纤维化过程中的作用.方法 选用30只雄性Balb/c小鼠建立小鼠UUO模型(n=24)和假手术小鼠(n=6),术后第1、4、7和14天检测JAK-STAT磷酸化情况.另把18只雄性Balb/c小鼠随机分为假手术组、UUO模型组和治疗组,每组各6只.治疗组在建模前2 h开始给予选择性JAK2抑制剂AG490治疗,每天1次;模型组仅注射溶媒.术后第14天处死动物.组织学评估肾小管损伤和.肾间质纤维化程度;免疫组化检测肾脏巨噬细胞浸润和α-SMA表达;RT-PCR检测Ⅲ型胶原和单核细胞趋化蛋白(MCP)1 mRNA表达;Western印迹检测JAK2和STATl磷酸化.结果 JAK2-STAT1在UUO模型中被激活,其磷酸化水平与病情、肾小管组织学损害以及.肾间质纤维化相一致.AG490能显著抑制JAK2和STAT1的磷酸化(P<0.01).AG490治疗显著减轻肾小管损害[(21.7±1.7)%比(49.4±1.0)%]和肾间质纤维化(1.0±0.1比2.3±0.2)、α-SMA表达(0.9±0.1比2.1±0.2)和巨噬细胞积聚[(13.3±1.6)细胞/HPF比(34.4±1.0)细胞/HPF](均P<0.01).AG490治疗显著抑制Ⅲ型胶原和MCP-1 mRNA表达.结论 JAK-STAT信号通路在肾小管间质炎性反应和纤维化中发挥重要作用.
目的 探討Janus蛋白酪氨痠激酶-信號轉導子和轉錄激活子(JAK-STAT)通路在小鼠單側輸尿管梗阻(UUO)模型.腎間質纖維化過程中的作用.方法 選用30隻雄性Balb/c小鼠建立小鼠UUO模型(n=24)和假手術小鼠(n=6),術後第1、4、7和14天檢測JAK-STAT燐痠化情況.另把18隻雄性Balb/c小鼠隨機分為假手術組、UUO模型組和治療組,每組各6隻.治療組在建模前2 h開始給予選擇性JAK2抑製劑AG490治療,每天1次;模型組僅註射溶媒.術後第14天處死動物.組織學評估腎小管損傷和.腎間質纖維化程度;免疫組化檢測腎髒巨噬細胞浸潤和α-SMA錶達;RT-PCR檢測Ⅲ型膠原和單覈細胞趨化蛋白(MCP)1 mRNA錶達;Western印跡檢測JAK2和STATl燐痠化.結果 JAK2-STAT1在UUO模型中被激活,其燐痠化水平與病情、腎小管組織學損害以及.腎間質纖維化相一緻.AG490能顯著抑製JAK2和STAT1的燐痠化(P<0.01).AG490治療顯著減輕腎小管損害[(21.7±1.7)%比(49.4±1.0)%]和腎間質纖維化(1.0±0.1比2.3±0.2)、α-SMA錶達(0.9±0.1比2.1±0.2)和巨噬細胞積聚[(13.3±1.6)細胞/HPF比(34.4±1.0)細胞/HPF](均P<0.01).AG490治療顯著抑製Ⅲ型膠原和MCP-1 mRNA錶達.結論 JAK-STAT信號通路在腎小管間質炎性反應和纖維化中髮揮重要作用.
목적 탐토Janus단백락안산격매-신호전도자화전록격활자(JAK-STAT)통로재소서단측수뇨관경조(UUO)모형.신간질섬유화과정중적작용.방법 선용30지웅성Balb/c소서건립소서UUO모형(n=24)화가수술소서(n=6),술후제1、4、7화14천검측JAK-STAT린산화정황.령파18지웅성Balb/c소서수궤분위가수술조、UUO모형조화치료조,매조각6지.치료조재건모전2 h개시급여선택성JAK2억제제AG490치료,매천1차;모형조부주사용매.술후제14천처사동물.조직학평고신소관손상화.신간질섬유화정도;면역조화검측신장거서세포침윤화α-SMA표체;RT-PCR검측Ⅲ형효원화단핵세포추화단백(MCP)1 mRNA표체;Western인적검측JAK2화STATl린산화.결과 JAK2-STAT1재UUO모형중피격활,기린산화수평여병정、신소관조직학손해이급.신간질섬유화상일치.AG490능현저억제JAK2화STAT1적린산화(P<0.01).AG490치료현저감경신소관손해[(21.7±1.7)%비(49.4±1.0)%]화신간질섬유화(1.0±0.1비2.3±0.2)、α-SMA표체(0.9±0.1비2.1±0.2)화거서세포적취[(13.3±1.6)세포/HPF비(34.4±1.0)세포/HPF](균P<0.01).AG490치료현저억제Ⅲ형효원화MCP-1 mRNA표체.결론 JAK-STAT신호통로재신소관간질염성반응화섬유화중발휘중요작용.
Objective To study the role of JAK-STAT singal transduction pathway in the interstitial fibrosis of unilateral ureter obstruction (UUO)mice. Methods Mice UUO model was established and the phosphorylation of JAK-STAT was examined at day 1,4,7 and 14 after ligation of the ureter.Mice in the treatment group were treated with daily injection of selective JAK2 inhibitor AG490 starting 2 h before ureter ligation until sacrifice while vehicle alone was given to mice in the model control group.Mice were sacrificed at day 14 after the establishment of model.Renal tubular lesion and interstitial fibrosis were assessed on paraffin section.Immunohistochemistry was used to detect renal macrophage infihration and α-SMA expression.The expression of collagen Ⅲ and MCP-1 mRNA was measured by RT-PCR.Phosphorylation of JAK2and STAT1 was examined by Western blotting. Results JAK2-STAT1 signaling transduction pathway was activated in UUO model.The activation of JAK2-STAT1 was closely correlated with the progression of renal injury,tubular histological lesions and interstitial fibrosis.AG490 treatment significantly inhibited the phosphorylation of JAK2 and STAT1 (P<0.01).AG490 treatment also significantly reduced tubular lesions[(21.7 ±1.7)% vs (49.4±1.0)%]and interstitial fibrosis(1.0±0.1 vs 2.3±0.2),α-SMA expression(0.9±0.1 vs 2.1±0.2)and maerophage accumulation[(13.3±1.6)cells/HPF vs (34.4±1.0)cells/HPF](all P<0.01).In addition,AG490 significantly inhibited the expression of collagen Ⅲ and MCP-1 mRNA. Conclusion JAK-STAT signaling plays an important role in renal tubulointerstitial inflammation and fibrosis.