Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion-induced injury through the B2R-Raf-MEK1/2-ERK1/2 pathway.
We have documented that tissue kallikrein (TK) prevents neurons from hypoxia/reoxygenation injury through the B2R-ERK1/2 pathway and the antihypoxic function of TK through Homer1b/c-ERK1/2 signaling pathways. The present study investigates the molecular mechanisms of exogenous TK activation of the B2R-ERK1/2 pathway through the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module in vivo. The cresyl violet staining results indicated that exogenous TK protected the rat hippocampal CA1 neurons against cerebral ischemia/reperfusion (I/R) injury. The immunoprecipitation (IP) and immunoblotting (IB) results revealed that exogenous TK upregulated the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and upregulated the phosphorylation of Raf (p-Raf), MEK1/2 (p-MEK1/2), and ERK1/2 (p-ERK1/2). Meanwhile, exogenous TK upregulated the expression of nuclear factor-κB (NF-κB), depressed the release of cytochrome c (Cyt c) and bax from mitochondria to the cytosol, and depressed the activation of caspase-3. Take together, our results suggest that exogenous TK attenuated the cerebral I/R induced rat hippocampal CA1 neurons injury through activating the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and that the activated B2R-Raf-MEK1/2 signaling module could upregulate the expression of NF-κB, decrease the release of cytochrome c and bax from mitochondria to the cytosol, and depress the activation of caspase-3.
Department of Neurology, Huashan hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Zheng
Z
Wang
Xiang
X
Han
Mei
M
Cui
Kun
K
Fang
Zhengyu
Z
Lu
Qiang
Q
Dong
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology; D009474:Neurons / Q000187:drug effects*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D020840:Tissue Kallikreins / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048490:raf Kinases / Q000378:metabolism
C000605257:Arrb2 protein, rat; D019390:Arrestins; D020319:Oligodeoxyribonucleotides, Antisense; D051028:bcl-2-Associated X Protein; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D045304:Cytochromes c; D048490:raf Kinases; D020840:Tissue Kallikreins; D053148:Caspase 3
ERK1/2; bradykinin 2 receptor; cerebral ischemia; hippocampal CA1 neuron; tissue kallikrein