title: Kinin-B2 receptor activity determines the differentiation fate of neural stem cells.
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 β3-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 β3-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.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil 05508-000.
authors.forename: Cleber A
authors.initials: CA
authors.lastname: Trujillo
authors.forename: Priscilla D
authors.initials: PD
authors.lastname: Negraes
authors.forename: Telma T
authors.initials: TT
authors.lastname: Schwindt
authors.forename: Claudiana
authors.initials: C
authors.lastname: Lameu
authors.forename: Cassiano
authors.initials: C
authors.lastname: Carromeu
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Débora M
authors.initials: DM
authors.lastname: Cerqueira
authors.forename: Micheli M
authors.initials: MM
authors.lastname: Pillat
authors.forename: Héllio D N
authors.initials: HD
authors.lastname: de Souza
authors.forename: Lauro T
authors.initials: LT
authors.lastname: Turaça
authors.forename: José G
authors.initials: JG
authors.lastname: Abreu
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043782:Receptor, Bradykinin B2