Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic
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ORIGINAL ARTICLE
Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats Hongfei Sang 1,2 & Zhongming Qiu 3 & Jin Cai 1,4 & Wenya Lan 5 & Linjie Yu 6 & Hao Zhang 1 & Min Li 1 & Yi Xie 1 & Ruibing Guo 1 & Ruidong Ye 1 & Xinfeng Liu 1 & Ling Liu 1 & Renliang Zhang 1
Received: 1 March 2017 / Revised: 27 June 2017 / Accepted: 29 June 2017 # Springer Science+Business Media, LLC 2017
Abstract Hemorrhagic transformation (HT) is a major complication of ischemic stroke and further deteriorates neurological outcomes. Bradykinin 1 receptor (B1R) has been proven to mediate vasculo-toxicity in various experimental models. However, its role in the development of HT after stroke remains unclear. We detected the B1R expression in brain tissues with or without HT in a rat model of cerebral ischemia/reperfusion (I/R) with type 1 diabetes, showing higher B1R expression in the hemorrhagic areas than the ischemic tissues. Then, B1R agonist or antagonist was administrated intravenously just before reperfusion to investigate its effect on HT and the
Hongfei Sang, Zhongming Qiu, and Jin Cai contributed equally to this work and shared first authorship * Ling Liu [email protected] * Renliang Zhang [email protected] 1
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, China
2
Department of Neurology, Geriatrics Hospital of Hangzhou City, Province, Zhejiang, Hangzhou 310022, China
3
Department of Neurology, The 117th Hospital of PLA, Province, Zhejiang, Hangzhou 310013, China
4
Department of Geriatrics, The 455th Hospital of PLA, Shanghai 200052, China
5
Department of Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
6
Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, China
underlying molecular mechanism. Administration of low (300 nmol/kg) or high (1 μmol/kg) dose of B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood-brain-barrier (BBB) integrity after reperfusion for 8 h whereas the 300 nmol/kg of B1R agonist aggravated these outcomes, though only the high does of B1R antagonist affected the infarction volume. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased by B1R activation but decreased by B1R inhibition, which mediated B1R toxicity on BBB disruption and ischemia-related HT. Furthermore, B1R activation facilitated the mRNA and protein expressions of MMP-9 in the hemorrhagic tissues, and these increases were blocked by both ERK inhibitor U0126 and NF-κB inhibitor PDTC. U0126 also remarkably decreased the B1R-induced NF-κB/p65 activation. We concluded that upregulated B1R may contribute to early HT after I/R in type 1 diabetic rats via ERK1/2/NF-κB/MMP9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients. Keywords Type 1 diabe
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