title: Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway.
abstract: Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157-an inhibitor of PERK-effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy.
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Bohan.Wang@ucsf.edu.
authors.forename: Bohan
authors.initials: B
authors.lastname: Wang
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. ninghongxiu@gmail.com.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Ning
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Amanda.Reed-Maldonado@ucsf.edu.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Reed-Maldonado
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Jun.Zhou@ucsf.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Yajun.Ruan@ucsf.edu.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Tie.Zhou@ucsf.edu.
authors.forename: Tie
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. HsunShuan.Wang@ucsf.edu.
authors.forename: Hsun Shuan
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. ByungSeok.Oh@ucsf.edu.
authors.forename: Byung Seok
authors.initials: BS
authors.lastname: Oh
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. Lia.Banie@ucsf.edu.
authors.forename: Lia
authors.initials: L
authors.lastname: Banie
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. glin@urology.ucsf.edu.
authors.forename: Guiting
authors.initials: G
authors.lastname: Lin
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA. tom.lue@ucsf.edu.
authors.forename: Tom F
authors.initials: TF
authors.lastname: Lue
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D004195:Disease Models, Animal; D020868:Gene Silencing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010413:Penis / Q000378:metabolism; D059348:Peripheral Nerve Injuries; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects; D000069453:Ultrasonic Waves; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000597302:GSK2656157; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D051701:Activating Transcription Factor 4; D019892:eIF-2 Kinase; D000225:Adenine
keywords: PERK/ATF4 pathway; Schwann cells; brain-derived neurotrophic factor; low-intensity extracorporeal shock wave treatment