title: Tissue Kallikrein Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the B2R-ERK1/2-CREB-Bcl-2 Signaling Pathway in Diabetic Rats.
abstract: Diabetes mellitus (DM) substantially increases the risk of ischemic stroke and reduces the tolerance to ischemic insults. Tissue kallikrein (TK) has been demonstrated to protect neurons from ischemia/reperfusion (I/R) injury in orthoglycemic model by activating the bradykinin B2 receptor (B2R). Considering the differential effects of B2R or bradykinin B1 receptor (B1R) on cardioprotection and neuroprotection in I/R with or without diabetes, this study was designed to investigate the role of TK during cerebral I/R injury in streptozotocin-induced diabetic rats. Intravenous injection of TK inhibited apoptosis in neurons, alleviated edema and inflammatory reactions after focal cerebral I/R, significantly reduced the infarct volume, and improved functional recovery. These beneficial effects were accompanied by activation of the extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding (CREB), and Bcl-2 signal proteins. Inhibition of the B2R or ERK1/2 pathway abated the effects of TK, whereas an antagonist of B1R enhanced the effects. These findings reveal that the neuroprotective effect of TK against cerebral I/R injury in streptozotocin-induced diabetic rats mainly involves the enhancement of B2R and ERK1/2-CREB-Bcl-2 signaling pathway activity.
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China; Department of Neurology, Maanshan Municipal People's Hospital, Maanshan, Anhui 243000, China.
authors.forename: Ruifeng
authors.identifier: 0000-0002-6493-9776
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Neurology, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu 210002, China.
authors.forename: Kunxiong
authors.initials: K
authors.lastname: Yuan
authors.affiliation: Department of Orthopedics, Maanshan Municipal People's Hospital, Maanshan, Anhui 243000, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Department of Biostatistics, School of Public Health and Tropical Medicine, Southern Medical University, 510515 Guangzhou, China.
authors.forename: Lizhi
authors.identifier: 0000-0001-7460-0787
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Yunyun
authors.identifier: 0000-0003-1353-2295
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Gelin
authors.identifier: 0000-0002-6194-0341
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang