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  • Wnt Signaling Regulates Blood Pressure by Downregulating a GSK-3β-Mediated Pathway to Enhance Insulin Signaling in the Central Nervous System.

Wnt Signaling Regulates Blood Pressure by Downregulating a GSK-3β-Mediated Pathway to Enhance Insulin Signaling in the Central Nervous System.

Diabetes (2015-04-18)
Pei-Wen Cheng, Ying-Ying Chen, Wen-Han Cheng, Pei-Jung Lu, Hsin-Hung Chen, Bo-Rong Chen, Tung-Chen Yeh, Gwo-Ching Sun, Michael Hsiao, Ching-Jiunn Tseng
RESUMEN

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.

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Anti-Active-β-Catenin (Anti-ABC) Antibody, clone 8E7, clone 8E7, Upstate®, from mouse
Sigma-Aldrich
Anti-phospho-GSK3β (Ser9) Antibody, clone 2D3, clone 2D3, Upstate®, from mouse
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Anti-IRS1 Antibody, clone 58-10C-31, rabbit monoclonal, clone 58-10C-31, from rabbit