TY - JOUR
T1 - Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice
T2 - differential effects for B1 and B2 receptors
AU - Acuña, María José
AU - Salas, Daniela
AU - Córdova-Casanova, Adriana
AU - Cruz-Soca, Meilyn
AU - Céspedes, Carlos
AU - Vio, Carlos P.
AU - Brandan, Enrique
N1 - Publisher Copyright:
© 2018, The International CCN Society.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeu8BK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-β and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle.
AB - The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeu8BK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-β and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle.
KW - Bradykinin receptors B1 and B2
KW - Fibrosis
KW - Inflammation
KW - Kallikrein kinin system
KW - Muscular dystrophy
UR - http://www.scopus.com/inward/record.url?scp=85038248946&partnerID=8YFLogxK
U2 - 10.1007/s12079-017-0439-x
DO - 10.1007/s12079-017-0439-x
M3 - Article
AN - SCOPUS:85038248946
SN - 1873-9601
VL - 12
SP - 589
EP - 601
JO - Journal of Cell Communication and Signaling
JF - Journal of Cell Communication and Signaling
IS - 3
ER -