Kinin-B2 Receptor Activity Determines the Differentiation Fate of Neural Stem Cells

Kinin-B2 Receptor Activity Determines the Differentiation Fate of Neural Stem Cells

Author Trujillo, Cleber A. Google Scholar
Negraes, Priscilla D. Google Scholar
Schwindt, Telma Tiemi Autor UNIFESP Google Scholar
Lameu, Claudiana Google Scholar
Carromeu, Cassiano Google Scholar
Muotri, Alysson R. Google Scholar
Pesquero, João Bosco Autor UNIFESP Google Scholar
Cerqueira, Debora M. Google Scholar
Pillat, Micheli M. Google Scholar
Souza, Hellio D. N. de Google Scholar
Turaça, Lauro Thiago Autor UNIFESP Google Scholar
Abreu, Jose G. Google Scholar
Ulrich, Alexander Henning Autor UNIFESP Google Scholar
Institution Universidade de São Paulo (USP)
Univ Calif San Diego
Universidade Federal de São Paulo (UNIFESP)
Universidade Federal do Rio de Janeiro (UFRJ)
Abstract Bradykinin is not only important for inflammation and blood pressure regulation, but also involved in neuromodulation and neuroprotection. Here we describe novel functions for bradykinin and the kinin-B2 receptor (B2BkR) in differentiation of neural stem cells. in the presence of the B2BkR antagonist HOE-140 during rat neurosphere differentiation, neuron-specific beta 3-tubulin and enolase expression was reduced together with an increase in glial protein expression, indicating that bradykinin- induced receptor activity contributes to neurogenesis. in agreement, HOE-140 affected in the same way expression levels of neural markers during neural differentiation of murine P19 and human iPS cells. Kinin-B1 receptor agonists and antagonists did not affect expression levels of neural markers, suggesting that bradykinin-mediated effects are exclusively mediated via B2BkR. Neurogenesis was augmented by bradykinin in the middle and late stages of the differentiation process. Chronic treatment with HOE-140 diminished eNOS and nNOS as well as M1-M4 muscarinic receptor expression and also affected purinergic receptor expression and activity. Neurogenesis, gliogenesis, and neural migration were altered during differentiation of neurospheres isolated from B2BkR knock-out mice. Whole mount in situ hybridization revealed the presence of B2BkR mRNA throughout the nervous system in mouse embryos, and less beta 3-tubulin and more glial proteins were expressed in developing and adult B2BkR knock-out mice brains. As a underlying transcriptional mechanism for neural fate determination, HOE-140 induced up-regulation of Notch1 and Stat3 gene expression. Because pharmacological treatments did not affect cell viability and proliferation, we conclude that bradykinin-induced signaling provides a switch for neural fate determination and specification of neurotransmitter receptor expression.
Language English
Sponsor National Institutes of Health
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Provost's Office for Research of the University of São Paulo Programa de Incentivo a Pesquisa
International Rett Syndrome Foundation
Emerald Foundation
California Institute for Regenerative Medicine Grant
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number National Institutes of Health: 1-DP2-OD006495-01
FAPESP: 2006/61285-9
Provost's Office for Research of the University of São Paulo Programa de Incentivo a Pesquisa: 2011.1.9333.1.3
International Rett Syndrome Foundation: 2517
California Institute for Regenerative Medicine Grant: TR2-01814
Date 2012-12-28
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 287, n. 53, p. 44046-44061, 2012.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 44046-44061
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000312938600004

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