title: 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 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.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Cheng
authors.affiliation: Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Republic of China.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Republic of China.
authors.forename: Hsin-Hung
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
authors.forename: Bo-Rong
authors.initials: BR
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
authors.forename: Tung-Chen
authors.initials: TC
authors.lastname: Yeh
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Republic of China.
authors.forename: Gwo-Ching
authors.initials: GC
authors.lastname: Sun
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Republic of China.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China Institute of Clinical Medicine, National Yang-Ming University, Taipei, Republic of China Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Republic of China cjtseng@vghks.gov.tw.
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D051153:Wnt Proteins; D009569:Nitric Oxide; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3