According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevate...According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).展开更多
目的研究不同基因型Na-K-2Cl联合转运子1(NKCC1)小鼠的耳蜗和前庭器官的超微形态特点及其与听觉平衡功能的关系。方法采用电子显微镜对NKCC1+/+野生型鼠、NKCC1+/-杂合子鼠和NKCC1-/-基因敲除鼠的耳蜗基底膜和前庭椭圆囊进行观察,并应...目的研究不同基因型Na-K-2Cl联合转运子1(NKCC1)小鼠的耳蜗和前庭器官的超微形态特点及其与听觉平衡功能的关系。方法采用电子显微镜对NKCC1+/+野生型鼠、NKCC1+/-杂合子鼠和NKCC1-/-基因敲除鼠的耳蜗基底膜和前庭椭圆囊进行观察,并应用听觉脑干反应(ABR)检测各基因型鼠的听力和观察平衡表现。结果电镜观察显示NKCC1-/-鼠的边缘细胞体积明显缩小,边缘细胞与中间细胞之间空隙扩大成空泡样,并可见前庭膜贴附于边缘细胞的顶膜边缘上。NKCC1-/-鼠外毛细胞呈现为点状缺失,椭圆囊毛细胞仅有少许残留。NKCC1+/+鼠听力和平衡正常,ABR检测的短声阈值为23.13±3.78(dB SPL);NKCC1+/-鼠听力低于NKCC1+/+鼠,ABR短声阈值为38.49±12.29(dB SPL)。NKCC1+/+和NKCC1+/-鼠ABR的阈值在各个频率的差异均有极显著性意义(均P<0.01)。NKCC1-/-鼠呈现全聋并有平衡失调,ABR的各个频率在100 dB SPL均无反应。结论NKCC1基因在内耳表达的不同可以影响小鼠的听觉平衡功能并导致内耳形态改变;内耳形态改变也可作为基因缺失小鼠听觉平衡的形态学基础。展开更多
The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry a...The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry and toluidine blue staining, the localization of NKCCl in cochlea of the C57BL/6J mice and the cochlear histological changes in the NKCCl knockout mice were observed. It was found that the NKCCl was expressed mainly in the stria marginal cells and the fibrocytes in the inferior portion of the spiral ligament in the adult C57BL/6J mice. Subpopulation of the fibrocytes in the suprastrial region and the limbus was also moderately immunoreactive. While in the cochlea of the NKCCl knockout mice, Reissner＇s membrane was collapsed and scala media disappeared, accompanied with the loss of inner hair cells, outer hair cells and the support cells. The tunnel of Corti was often absent. All the findings suggested the localization of NKCCl in the cochlea was closely correlated with cochlear K^＋ cycling. Loss of NKCCl led to the destruction of the cochlear structures, and subsequently influenced the physiological function of cochlea.展开更多
文摘According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).
文摘目的研究不同基因型Na-K-2Cl联合转运子1(NKCC1)小鼠的耳蜗和前庭器官的超微形态特点及其与听觉平衡功能的关系。方法采用电子显微镜对NKCC1+/+野生型鼠、NKCC1+/-杂合子鼠和NKCC1-/-基因敲除鼠的耳蜗基底膜和前庭椭圆囊进行观察,并应用听觉脑干反应(ABR)检测各基因型鼠的听力和观察平衡表现。结果电镜观察显示NKCC1-/-鼠的边缘细胞体积明显缩小,边缘细胞与中间细胞之间空隙扩大成空泡样,并可见前庭膜贴附于边缘细胞的顶膜边缘上。NKCC1-/-鼠外毛细胞呈现为点状缺失,椭圆囊毛细胞仅有少许残留。NKCC1+/+鼠听力和平衡正常,ABR检测的短声阈值为23.13±3.78(dB SPL);NKCC1+/-鼠听力低于NKCC1+/+鼠,ABR短声阈值为38.49±12.29(dB SPL)。NKCC1+/+和NKCC1+/-鼠ABR的阈值在各个频率的差异均有极显著性意义(均P<0.01)。NKCC1-/-鼠呈现全聋并有平衡失调,ABR的各个频率在100 dB SPL均无反应。结论NKCC1基因在内耳表达的不同可以影响小鼠的听觉平衡功能并导致内耳形态改变;内耳形态改变也可作为基因缺失小鼠听觉平衡的形态学基础。
文摘The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry and toluidine blue staining, the localization of NKCCl in cochlea of the C57BL/6J mice and the cochlear histological changes in the NKCCl knockout mice were observed. It was found that the NKCCl was expressed mainly in the stria marginal cells and the fibrocytes in the inferior portion of the spiral ligament in the adult C57BL/6J mice. Subpopulation of the fibrocytes in the suprastrial region and the limbus was also moderately immunoreactive. While in the cochlea of the NKCCl knockout mice, Reissner＇s membrane was collapsed and scala media disappeared, accompanied with the loss of inner hair cells, outer hair cells and the support cells. The tunnel of Corti was often absent. All the findings suggested the localization of NKCCl in the cochlea was closely correlated with cochlear K^＋ cycling. Loss of NKCCl led to the destruction of the cochlear structures, and subsequently influenced the physiological function of cochlea.
