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Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors

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Journal of Cell Communication and Signaling Aims and scope

Abstract

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.

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Fig. 1: Bradykinin receptor blockade increases damage and fibrosis in mdx muscle
Fig. 2: Bradykinin receptor blockade increases TGF-β and phospho-Smad3 positive cells
Fig. 3: Bradykinin receptor blockade increases CTGF/CCN2 mRNA and protein levels
Fig. 4: Bradykinin receptor blockade increases inflammatory CD68+ cells and tnf-α mRNA levels inmdx muscle
Fig. 5: B2R blockade reduces strength in diaphragm and tibial anterior muscle of mdx mice
Fig. 6

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Abbreviations

Ang-II:

Angiotensin-II

Ang-(1–7):

Angiotensin-(1–7)

ACE:

Angiotensin converting enzyme

AT1:

Angiotensin receptor 1

BK:

Bradykinin

B1R:

Bradykinin Receptor 1

B2R:

Bradykinin Receptor 2

CTGF/CCN-2:

Connective tissue growth factor

DALBK:

DesArg9Leu8-Bradykinin

DMD:

Duchenne muscular dystrophy

ECM:

Extracellular matrix

KKS:

Kallikrein kinin system

LTBP:

Latent TGF-β-binding protein

RAS:

Renin Angiotensin system

TGF-β:

Transforming growth factor type-β

TNF-α:

Tumor necrosis factor alpha

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Acknowledgements

The authors are grateful to Victor Troncoso, Tamara Ramirez, Darling Vera, Lina Correa and Eduardo Ramirez for technical assistance.

Funding

FONDECYT Grant 3,140,323 to M.J.A and 1,150,106 to EB; CARE-PFB-12/2007 grant to E.B. and C.P.V and SQM grant to C.P.V. The funding agencies had no role in the design of the study, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Centro de Envejecimiento y Regeneración, CARE Chile UC y Departamento de Biología Celular y Molecular, Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    María José Acuña, Daniela Salas, Adriana Córdova-Casanova, Meilyn Cruz-Soca, Carlos Céspedes, Carlos P. Vio & Enrique Brandan

  2. Centro de Biología y Química Aplicada (CIBQA), Universidad Bernardo O Higgins, Santiago, Chile

    María José Acuña

  3. Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    Carlos P. Vio & Enrique Brandan

  4. Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Libertador Bernardo O’Higgins 340, 8331150, Santiago, Chile

    Carlos P. Vio & Enrique Brandan

Authors
  1. María José Acuña
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  2. Daniela Salas
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  3. Adriana Córdova-Casanova
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  4. Meilyn Cruz-Soca
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  5. Carlos Céspedes
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  6. Carlos P. Vio
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  7. Enrique Brandan
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Contributions

M.J.A., C.V. and E.B. conceived the concepts, designed the study and wrote the manuscript. M.J.A. performed the experiments, drafted the manuscript and analyzed the data. A.C-C. helped with western blot and Sirius red quantitation analyses. C.C. did the immunohistochemical stain for CTGF/CCN2, M.C-S and D.S. did the qPCR experiments.

Corresponding authors

Correspondence to Carlos P. Vio or Enrique Brandan.

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Electronic supplementary material

Supplemental Figure 1

BK receptors blockade increases total collagen staining. Sirius red staining reconstruction of gastrocnemius (GAST) from mdx control, mdx HOE-140 and mdx DALBK treated mice. The photographs were taken under polarized light. The red-orange color corresponds to thicker collagen fibers, the yellow to intermediate and the greenish color to thinner. (PDF 1576 kb)

Supplemental Figure 2

Fibronectin is increased in HOE-140 treated mice. A) GAST cryosections were immunostained for fibronectin (FN) to asses for tissue fibrosis. Bar 100 μm. B) and D) are representative western blot analysis for FN from total GAST muscle extracts GAPDH was used as the loading control: B) wild type, mdx control and mdx HOE-140, D) wild type, mdx control and mdx DALBK. C) and E) Quantitation of western blots analyses for FN. One way ANOVA *p < 0,05 vs wild type; ϕ p < 0,05 vs mdx control; n = 4 mdx control; n = 6 mdx HOE-140, n = 6 mdx DALBK and WT n = 5. (PDF 6081 kb)

Supplemental figure 3

CCN1 and CCN3 mRNA levels are decreased in dystrophic muscle treated with HOE-140. Total RNA purified from TA was analyzed by qPCR for ccn1 A) and B) and ccn3 C) and D). 18 s was used as reference gene. T-test *p < 0,05 vs mdx control; n = 6 mdx control; n = 7 mdx HOE-140, n = 6 mdx DALBK (PDF 223 kb)

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Acuña, M.J., Salas, D., Córdova-Casanova, A. et al. Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors. J. Cell Commun. Signal. 12, 589–601 (2018). https://doi.org/10.1007/s12079-017-0439-x

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