EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogen...EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogenesis remains to be explored. In this study, we found that EZH2 and H3K27me3 were highly expressed in the cultured renal fibroblastsand thefibrotic kidney from mice with unilateral ureteral obstruction and from humans withchronic kidney disease. Pharmacological inhibition of EZH2 with3-deazaneplanocin A（3-DZNeP） and GSK126, or silen- cing of EZH2 with its specific siRNA, inhibited serum-and TGF[31-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of oL-SMA in the obstructed kidney. Mechanistically,3-DZNeP inhibited expression of type I TGF-β1 receptor and phosphoryl- ation of Smad3, along with preservation of Smad-7 expression. 3-DZNeP treatment also suppressed phosphorylation of the EGF and PDGFβ receptors as well as STAT3 and ERK1/2, two signaling pathways associated with renal fi- brosis in the injured kidney. Moreover, EZH2 inhibition increased expression of PTEN, a protein tyrosine phospha- tase associated with the dephosphorylation of multiple tyrosine kinase receptors, in the kidney after ureteral ligation and in serum-stimulated renal interstitial fibroblasts. Finally, inhibition of PTEN reversed the antagonistic effect of 3-DZNeP on myofibroblast activation. These results uncovered the important role of EZH2in mediating activation of renal fibroblasts and the development of renal fibrosis through the activation of multiple profibrotic signaling path- ways. Targeted inhibition of EZH2 could therefore represent a novel therapy to treat chronic kidney disease.展开更多
目的检测组蛋白甲基化转移酶2(SET and MYND domain containing 2,SMYD2)在糖尿病小鼠肾组织中的表达变化,分析其与上皮细胞⁃间充质细胞转化(epithelial⁃mesenchymal transformation,EMT)的相关性,为临床上治疗糖尿病肾病(diabetic neph...目的检测组蛋白甲基化转移酶2(SET and MYND domain containing 2,SMYD2)在糖尿病小鼠肾组织中的表达变化,分析其与上皮细胞⁃间充质细胞转化(epithelial⁃mesenchymal transformation,EMT)的相关性,为临床上治疗糖尿病肾病(diabetic nephropathy,DN)提供新的方向。方法24只雄性C57BL/6小鼠随机分为正常对照(NC)组、DM12周组、DM24周组和DM28周组,每组6只。采用腹腔注射链脲佐菌素(streptozotocin,STZ)复制DM小鼠模型,处死小鼠后收集血清和肾组织,全自动生化分析仪测血糖(BG)、血肌酐(Scr)和尿素氮(BUN);利用HE和Masson染色进行肾脏病理分析;应用Western blot方法检测α⁃平滑肌肌动蛋白(α⁃SMA)、波形蛋白(Vimentin)、SMYD2、转化生长因子⁃β1(TGF⁃β1)和E⁃钙黏素(E⁃cadherin)的表达。结果与NC组相比,DM组小鼠BG、Scr和BUN水平均明显增加(P<0.05),24周组和28周组肾组织出现明显的病理改变和纤维增生,α⁃SMA、Vimentin、SMYD2和TGF⁃β1蛋白表达增加(P<0.05),E⁃cadherin蛋白表达减少(P<0.05),其中SMYD2与E⁃cadherin的表达呈负相关,与α⁃SMA,Vimentin和TGF⁃β1的表达呈正相关。结论SMYD2在DM小鼠肾组织中表达上调,推测其可能和TGF⁃β1表达上调共同参与EMT的发生,进而参与调控DN的发生发展。展开更多
文摘目的探讨组蛋白H2B单泛素化(histone H2B monoubiquitination,u H2B)在原发性结肠腺癌中的表达及其与临床病理参数的关系。方法采用免疫组化ABC法检测116例原发性结肠腺癌及15例正常结肠黏膜组织中u H2B的表达,并复习相关文献。结果 u H2B在低分化原发性结肠腺癌中的阳性率(19.4%,6/31)显著低于高+中分化腺癌(49.4%,42/85)及正常结肠黏膜组织(86.7%,13/15),差异有统计学意义(P<0.05)。u H2B与肿瘤分化程度、Dukes分期、TNM分期及淋巴结转移相关(P<0.05),与患者性别、年龄无关(P>0.05)。结论 u H2B作为一种抑癌因子可能与原发性结肠腺癌的恶化过程密切相关。其可能会成为原发性结肠腺癌早期检测、治疗及预后评估的新分子生物学标志并应用于临床,而其在结肠腺癌中的具体作用机制仍有待进一步研究。
文摘EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogenesis remains to be explored. In this study, we found that EZH2 and H3K27me3 were highly expressed in the cultured renal fibroblastsand thefibrotic kidney from mice with unilateral ureteral obstruction and from humans withchronic kidney disease. Pharmacological inhibition of EZH2 with3-deazaneplanocin A（3-DZNeP） and GSK126, or silen- cing of EZH2 with its specific siRNA, inhibited serum-and TGF[31-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of oL-SMA in the obstructed kidney. Mechanistically,3-DZNeP inhibited expression of type I TGF-β1 receptor and phosphoryl- ation of Smad3, along with preservation of Smad-7 expression. 3-DZNeP treatment also suppressed phosphorylation of the EGF and PDGFβ receptors as well as STAT3 and ERK1/2, two signaling pathways associated with renal fi- brosis in the injured kidney. Moreover, EZH2 inhibition increased expression of PTEN, a protein tyrosine phospha- tase associated with the dephosphorylation of multiple tyrosine kinase receptors, in the kidney after ureteral ligation and in serum-stimulated renal interstitial fibroblasts. Finally, inhibition of PTEN reversed the antagonistic effect of 3-DZNeP on myofibroblast activation. These results uncovered the important role of EZH2in mediating activation of renal fibroblasts and the development of renal fibrosis through the activation of multiple profibrotic signaling path- ways. Targeted inhibition of EZH2 could therefore represent a novel therapy to treat chronic kidney disease.
文摘目的检测组蛋白甲基化转移酶2(SET and MYND domain containing 2,SMYD2)在糖尿病小鼠肾组织中的表达变化,分析其与上皮细胞⁃间充质细胞转化(epithelial⁃mesenchymal transformation,EMT)的相关性,为临床上治疗糖尿病肾病(diabetic nephropathy,DN)提供新的方向。方法24只雄性C57BL/6小鼠随机分为正常对照(NC)组、DM12周组、DM24周组和DM28周组,每组6只。采用腹腔注射链脲佐菌素(streptozotocin,STZ)复制DM小鼠模型,处死小鼠后收集血清和肾组织,全自动生化分析仪测血糖(BG)、血肌酐(Scr)和尿素氮(BUN);利用HE和Masson染色进行肾脏病理分析;应用Western blot方法检测α⁃平滑肌肌动蛋白(α⁃SMA)、波形蛋白(Vimentin)、SMYD2、转化生长因子⁃β1(TGF⁃β1)和E⁃钙黏素(E⁃cadherin)的表达。结果与NC组相比,DM组小鼠BG、Scr和BUN水平均明显增加(P<0.05),24周组和28周组肾组织出现明显的病理改变和纤维增生,α⁃SMA、Vimentin、SMYD2和TGF⁃β1蛋白表达增加(P<0.05),E⁃cadherin蛋白表达减少(P<0.05),其中SMYD2与E⁃cadherin的表达呈负相关,与α⁃SMA,Vimentin和TGF⁃β1的表达呈正相关。结论SMYD2在DM小鼠肾组织中表达上调,推测其可能和TGF⁃β1表达上调共同参与EMT的发生,进而参与调控DN的发生发展。
