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Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats

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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 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/MMP-9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients.

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Author notes

  1. Hongfei Sang, Zhongming Qiu, and ** Cai contributed equally to this work and shared first authorship

Authors and Affiliations

  1. Department of Neurology, **ling Hospital, Medical School of Nan**g University, 305 East Zhongshan Road, Nan**g, Jiangsu Province, 210002, China

    Hongfei Sang, ** Cai, Hao Zhang, Min Li, Yi **e, Ruibing Guo, Ruidong Ye, **nfeng Liu, Ling Liu & Renliang Zhang

  2. Department of Neurology, Geriatrics Hospital of Hangzhou City, Province, Zhejiang, Hangzhou, 310022, China

    Hongfei Sang

  3. Department of Neurology, The 117th Hospital of PLA, Province, Zhejiang, Hangzhou, 310013, China

    Zhongming Qiu

  4. Department of Geriatrics, The 455th Hospital of PLA, Shanghai, 200052, China

    ** Cai

  5. Department of Neurology, Nan**g Brain Hospital Affiliated to Nan**g Medical University, Nan**g, Jiangsu Province, 210029, China

    Wenya Lan

  6. Nan**g University School of Medicine, Nan**g, Jiangsu Province, 210002, China

    Linjie Yu

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  1. Hongfei Sang
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Correspondence to Ling Liu or Renliang Zhang.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81100870, 81400332) and Natural Science Foundation of Jiangsu Province (No. BK2011663).

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animal experimental procedures were conducted according to the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23, revised 1996) and conformed to the Institutional Animal Care and Use Committee of the Nan**g University

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Sang, H., Qiu, Z., Cai, J. et al. Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats. Transl. Stroke Res. 8, 597–611 (2017). https://doi.org/10.1007/s12975-017-0552-4

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