Cheng Pei-Wen, Chen Ying-Ying, Cheng Wen-Han, Lu Pei-Jung, Chen Hsin-Hung, Chen Bo-Rong, Yeh Tung-Chen, Sun Gwo-Ching, Hsiao Michael, Tseng Ching-Jiunn
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
Diabetes. 2015 Oct;64(10):3413-24. doi: 10.2337/db14-1439. Epub 2015 Apr 16.
Aberrant Wnt signaling appears to play an important role in the onset of diabetes. Moreover, the insulin signaling pathway is defective in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and fructose-fed rats. Nevertheless, the relationships between Wnt signaling and the insulin pathway and the related modulation of blood pressure (BP) in the central nervous system have yet to be established. The aim of this study was to investigate the potential signaling pathways involved in Wnt-mediated BP regulation in the NTS. Pretreatment with the LDL receptor-related protein (LRP) antagonist Dickkopf-1 (DKK1) significantly attenuated the Wnt3a-induced depressor effect and nitric oxide production. Additionally, the inhibition of LRP6 activity using DKK1 significantly abolished Wnt3a-induced glycogen synthase kinase 3β (GSK-3β)(S9), extracellular signal-regulated kinases 1/2(T202/Y204), ribosomal protein S6 kinase(T359/S363), and Akt(S473) phosphorylation; and increased insulin receptor substrate 1 (IRS1)(S332) phosphorylation. GSK-3β was also found to bind directly to IRS1 and to induce the phosphorylation of IRS1 at serine 332 in the NTS. By contrast, administration of the GSK-3β inhibitor TWS119 into the brain decreased the BP of hypertensive rats by enhancing IRS1 activity. Taken together, these results suggest that the GSK-3β-IRS1 pathway may play a significant role in Wnt-mediated central BP regulation.
异常的Wnt信号通路似乎在糖尿病的发病过程中起重要作用。此外，自发性高血压大鼠（SHR）和喂食果糖的大鼠孤束核（NTS）中的胰岛素信号通路存在缺陷。然而，Wnt信号通路与胰岛素通路之间的关系以及中枢神经系统中血压（BP）的相关调节作用尚未明确。本研究的目的是探讨NTS中Wnt介导的血压调节所涉及的潜在信号通路。用低密度脂蛋白受体相关蛋白（LRP）拮抗剂Dickkopf-1（DKK1）预处理可显著减弱Wnt3a诱导的降压作用和一氧化氮生成。此外，使用DKK1抑制LRP6活性可显著消除Wnt3a诱导的糖原合酶激酶3β（GSK-3β）（S9）、细胞外信号调节激酶1/2（T202/Y204）、核糖体蛋白S6激酶（T359/S363）和Akt（S473）的磷酸化；并增加胰岛素受体底物1（IRS1）（S332）的磷酸化。还发现GSK-3β可直接与IRS1结合，并诱导NTS中IRS1丝氨酸332位点的磷酸化。相比之下，向脑中注射GSK-3β抑制剂TWS119可通过增强IRS1活性降低高血压大鼠的血压。综上所述，这些结果表明GSK-3β-IRS1通路可能在Wnt介导的中枢血压调节中起重要作用。
