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

Abstract

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 3b (GSK-3b) 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-3b 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-3b inhibitor TWS119 into the brain decreased the BP of hypertensive rats by enhancing IRS1 activity. Taken together, these results suggest that the GSK-3b-IRS1 pathway may play a significant role in Wnt-mediated central BP regulation.The nucleus tractus solitarii (NTS), which is located in the dorsal medulla of the brainstem, is the primary site of blood pressure (BP) and sympathetic nerve activity modulation. The NTS participates in cardiovascular, gastric, and gustatory regulation. Our previous studies revealed that several neuromodulators are involved in BP control of the NTS, including insulin (1,2) and nitric oxide (NO) (3).Insulin is primarily produced by pancreatic b-cells. Margolis and Altszuler (4) reported that insulin can cross the blood-brain barrier, as demonstrated by sensitive and specific radioimmunoassay results. However, insulin mRNA and immunoreactive insulin are present in the rat central nervous system (5,6). The insulin receptor (IR) is a tetrameric glycoprotein that belongs to the receptor tyrosine kinase superfamily. Insulin can bind to the IR, leading to the autophosphorylation of the b-subunit of the IR at tyrosine residues, which induces the tyrosine phosphorylation of IR substrates (IRSs) (7). IRs/IRSs can activate the following two major signaling pathways: the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and the Ras-mitogenactivated protein kinase pathway. Insulin has also been implicated in the regulation of the baroreceptor reflex in the NTS (8,9). We previously found (1,2) that insulin is involved in the control of central BP via the PI3K-Akt-NO synthase (NOS) signaling pathway in the NTS.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations

“…[55] The Th1/Th2 pathway is involved in the regulation of immune responses[56] and has been linked to hypertension and atherosclerosis. [57, 58] The role of the immune system in the development of hypertension has been suggested in clinical studies and experimental animal models.…”

Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas

“…Wnt ligands are secreted glycoproteins that signal through Frizzled (FZD) receptor and low-density lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6) co-receptor, leading to downregulation of glycogen synthase kinase-3 (GSK-3) activity and the initiation of the canonical Wnt/β-catenin signaling cascade 33, 34. Activation of canonical Wnt signaling culminates in the cytoplasmic accumulation of β-catenin and its translocation to the nucleus where it complexes with transcription factors and coactivators to drive context-dependent target gene expression 35, 36.…”

Wnt signaling, a novel pathway regulating blood pressure? State of the art review

“…Interestingly, Wnt signaling in the NTS is defective in hypertension, as evidenced by decreased phosphorylation of LRP6 (activation) and GSK-3β (deactivation) in genetic (spontaneously hypertensive rats or SHR) and dietary (fructose fed mice) models of hypertension. It has been shown that intraventricular infusion of Wnt3a into the brains of SHR rats lowers BP, decreases heart rate, and increases nitric oxide release (59). This effect was reversed with the administration of Wnt antagonist Dickkopf-1 (DKK1) (59, 60).…”

“…It has been shown that intraventricular infusion of Wnt3a into the brains of SHR rats lowers BP, decreases heart rate, and increases nitric oxide release (59). This effect was reversed with the administration of Wnt antagonist Dickkopf-1 (DKK1) (59, 60). Similar results were obtained in the fructose-fed–induced hypertension model.…”

“…In another set of experiments, rats exhibit reduced BP and heart rate in response to insulin injection into the NTS (56). Wnt3a administration significantly increased downstream insulin signaling in the NTS of SHR rats and fructose-fed hypertensive rats (59). Further studies showed that the interaction between GSK3-β and IRS1 plays a central role in Wnt3a-mediated hypotensive effects in the NTS (59).…”