目的通过观察高果糖喂养大鼠肾组织中转化生长因子(TGF)-β1、纤溶酶原激活物抑制物(PAI)-1、肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6及NADPH氧化酶(Nox2)的变化,探讨高果糖喂养致大鼠脂质肾毒性中纤维化、炎症和氧化应激的作用及鹅去...目的通过观察高果糖喂养大鼠肾组织中转化生长因子(TGF)-β1、纤溶酶原激活物抑制物(PAI)-1、肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6及NADPH氧化酶(Nox2)的变化,探讨高果糖喂养致大鼠脂质肾毒性中纤维化、炎症和氧化应激的作用及鹅去氧胆酸(CDCA)的保护作用。方法将48只大鼠分为对照组,高果糖组、CDCA组,各16只。8、16 w时分批处死,检测各组大鼠的肾功能、空腹血糖(FPG)、血脂及24 h尿微量白蛋白(UMA);检测大鼠肾皮质甘油三酯(TG)含量;TGF-β1、PAI-I、TNF-α、IL-6及Nox2基因和蛋白的表达分别采用实时荧光定量PCR分析技术及Western印迹法。结果与对照组比较,高果糖组大鼠左肾重/体重(KW/BW),血中TG和极低密度脂蛋白(VLDL)水平明显升高,24 h UMA增加,肾组织中TG水平明显增高,且随时间延长而加重(P<0.05);TGF-β1、PAI-I、TNF-α、IL-6和Nox2基因及蛋白表达明显增加,且随时间延长其表达更多(P<0.01),CDCA组上述指标明显改善(P<0.05)。结论高果糖饮食喂养可导致大鼠高TG血症、高VLDL血症、高尿酸(UA)血症CDCA和UMA水平增加,可引起大鼠肾皮质TG蓄积。高果糖促使肾组织纤维化、炎症因子和氧化应激增强,进而导致肾脏损伤。CDCA通过下调纤维化、炎症因子及氧化应激指标的表达,减轻肾损伤。展开更多
Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (...Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2 (NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors. One such cryptic target is heme oxygenase I (HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).展开更多
文摘目的通过观察高果糖喂养大鼠肾组织中转化生长因子(TGF)-β1、纤溶酶原激活物抑制物(PAI)-1、肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6及NADPH氧化酶(Nox2)的变化,探讨高果糖喂养致大鼠脂质肾毒性中纤维化、炎症和氧化应激的作用及鹅去氧胆酸(CDCA)的保护作用。方法将48只大鼠分为对照组,高果糖组、CDCA组,各16只。8、16 w时分批处死,检测各组大鼠的肾功能、空腹血糖(FPG)、血脂及24 h尿微量白蛋白(UMA);检测大鼠肾皮质甘油三酯(TG)含量;TGF-β1、PAI-I、TNF-α、IL-6及Nox2基因和蛋白的表达分别采用实时荧光定量PCR分析技术及Western印迹法。结果与对照组比较,高果糖组大鼠左肾重/体重(KW/BW),血中TG和极低密度脂蛋白(VLDL)水平明显升高,24 h UMA增加,肾组织中TG水平明显增高,且随时间延长而加重(P<0.05);TGF-β1、PAI-I、TNF-α、IL-6和Nox2基因及蛋白表达明显增加,且随时间延长其表达更多(P<0.01),CDCA组上述指标明显改善(P<0.05)。结论高果糖饮食喂养可导致大鼠高TG血症、高VLDL血症、高尿酸(UA)血症CDCA和UMA水平增加,可引起大鼠肾皮质TG蓄积。高果糖促使肾组织纤维化、炎症因子和氧化应激增强,进而导致肾脏损伤。CDCA通过下调纤维化、炎症因子及氧化应激指标的表达,减轻肾损伤。
文摘Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2 (NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors. One such cryptic target is heme oxygenase I (HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).
