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In this study, we proposed that autophagy induction contributed to the neuroprotective mechanism of TK<\/jats:styled-content>. To validate this hypothesis, we investigated TK<\/jats:styled-content>\u2010induced autophagy and its signaling mechanisms in human SH<\/jats:styled-content>\u2010SY<\/jats:styled-content>5Y cells exposed to oxygen and glucose deprivation (OGD<\/jats:styled-content>). We found that TK<\/jats:styled-content> treatment enhanced autophagy induction, reflected by augmented LC<\/jats:styled-content>3 conversion and Beclin1 expression, decreased p62 levels and increased monomeric red fluorescent protein\u2010LC<\/jats:styled-content>3 puncta formation. Green fluorescent protein\u2010monomeric red fluorescent protein\u2010LC<\/jats:styled-content>3 adenovirus assay indicated that TK<\/jats:styled-content> maintained autophagic flux. Moreover, bafilomycin A1 (Baf.A1) caused obvious LC<\/jats:styled-content>3\u2010II<\/jats:styled-content> accumulation either in the presence or absence of TK<\/jats:styled-content>. Autophagy inhibition by Beclin1 knockdown or Baf.A1 treatment abrogated the neuroprotective effects of TK<\/jats:styled-content>. Mitogen\u2010activated protein kinase kinase 1\/2 (MEK1\/2)\/extracellular signal\u2010regulated kinase (ERK<\/jats:styled-content>)1\/2 and AMP\u2010activated protein kinase (AMPK<\/jats:styled-content>)\/tuberous sclerosis complex 2 (TSC<\/jats:styled-content>2)\/mammalian target of rapamycin (mTOR<\/jats:styled-content>) signaling were induced by OGD<\/jats:styled-content> stress and enhanced by TK<\/jats:styled-content>. MEK<\/jats:styled-content>\/ERK<\/jats:styled-content> inhibitor U0126 alone elevated autophagy in OGD<\/jats:styled-content> conditions, but impaired TK<\/jats:styled-content>\u2010induced autophagy. Blockade of AMPK<\/jats:styled-content>\/TSC<\/jats:styled-content>2\/mTOR<\/jats:styled-content> signaling by AMPK<\/jats:styled-content> inhibitor compound C and shRNA<\/jats:styled-content> mediated the knockdown of AMPK<\/jats:styled-content> \u03b11 and TSC<\/jats:styled-content>2 but abolished autophagy in SH<\/jats:styled-content>\u2010SY<\/jats:styled-content>5Y cells exposed to OGD<\/jats:styled-content> treated either with or without TK<\/jats:styled-content>. Moreover, B2R expression was up\u2010regulated by OGD<\/jats:styled-content> exposure. B2R knockdown attenuated autophagy and suppressed MEK<\/jats:styled-content>1\/2\/ERK<\/jats:styled-content>1\/2 and AMPK<\/jats:styled-content>\/TSC<\/jats:styled-content>2\/mTOR<\/jats:styled-content> signaling in OGD<\/jats:styled-content> conditions in either the presence or absence of TK<\/jats:styled-content>. In sum, we revealed the significance of B2R\u2010mediated MEK<\/jats:styled-content>\/ERK<\/jats:styled-content> and AMPK<\/jats:styled-content> signaling in autophagy induction under OGD<\/jats:styled-content> stress, and proposed novel mechanisms involved in the neuropotective function of TK<\/jats:styled-content> through B2R\u2010dependent regulation of autophagy.<\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nWe propose the depicted model for the neuroprotective mechanism of tissue kallikrein (TK) during OGD stress: TK enhances bradykinin B2 receptor (B2R)\u2010mediated MEK1\/2\/ERK1\/2 and AMPK\/TSC2\/mTOR signaling, thus inducing protective autophagy. The findings reported in this study should provide new evidence for the pro\u2010survival role of B2R\u2010mediated autophagy in cerebral ischemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13690","type":"journal-article","created":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T23:40:53Z","timestamp":1464824453000},"page":"208-220","source":"Crossref","is-referenced-by-count":30,"title":["Tissue kallikrein protects SH\u2010SY5Y neuronal cells against oxygen and glucose deprivation\u2010induced injury through bradykinin B2 receptor\u2010dependent regulation of autophagy induction"],"prefix":"10.1111","volume":"139","author":[{"given":"Yanping","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology Huashan Hospital State Key Laboratory of Medical Neurobiology Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengyu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurology Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital State Key Laboratory of Medical Neurobiology Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital State Key Laboratory of Medical Neurobiology Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuping","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital State Key Laboratory of Medical Neurobiology Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital State Key Laboratory of Medical Neurobiology Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,9,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416609112"},{"key":"e_1_2_7_3_1","first-page":"1","article-title":"Bioregulation of kinins: kallikreins, kininogens, and kininases","volume":"44","author":"Bhoola K. 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