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

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 fructosefed 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 3 beta (GSK-3 beta)(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-3 beta was also found to bind directly to IRS1 and to induce the phosphotylation of IRS1 at serine 332 in the NTS. By contrast, administration of the GSK-3 beta inhibitor TWS119 into the brain decreased the BP of hypertensive rats by enhancing IRS1 activity. Taken together, these results suggest that the GSK-3 beta-IRS1 pathway may play a significant role in Wnt-mediated central BP regulation.