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Kinin B1 receptor deficiency attenuates cisplatin-induced acute kidney injury by modulating immune cell migration

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Abstract

Cisplatin is a chemotherapeutic agent that causes severe renal dysfunction. The kinin B1 receptor has been associated with the migration of immune cells to injured tissue as well as with renal inflammation. To examine the role of the kinin B1 receptor in cisplatin-induced acute kidney injury, we used kinin B1 receptor knockout mice and treatment with a receptor antagonist before and after cisplatin administration. Cisplatin injection caused exacerbation of renal macrophage and neutrophil migration, higher levels of serum creatinine and blood urea, upregulation of B1 receptor mRNA and an increase in pro-inflammatory cytokines expression. B1 receptor knockout mice exhibited a reduction in serum creatinine and blood urea levels, diminished apoptosis, and decreased cisplatin-induced upregulation of inflammatory components. Moreover, treatment with the B1 receptor antagonist prior to cisplatin administration normalized serum creatinine, blood urea levels, protected from acute tubular necrosis, apoptosis-related genes, and prevented upregulation of pro-inflammatory cytokines. Thus, we propose that kinins have an important role in cisplatin-induced acute kidney injury by impairing immune cells migration to renal tissue during cisplatin nephrotoxicity.

Key message

  • Kinin B1 receptor is upregulated after cisplatin exposure.

  • Kinin B1 receptor deficiency diminishes the nephrotoxicity caused by cisplatin.

  • Kinin B1 receptor deficiency ameliorates the inflammatory response.

  • Kinin B1 receptor deficiency diminishes apoptosis caused by cisplatin.

  • Kinin B1 receptor antagonism ameliorates renal function after cisplatin injection.

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Acknowledgements

This work was supported by FAPESP (Fundação de Apoio a Pesquisa do Estado de São Paulo), grant 2011/03528-0.

Conflict of interest

All the authors declared no competing interests.

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Authors and Affiliations

  1. Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil

    Gabriel R. Estrela, Frederick Wasinski, Carolina C. Dias, Sandro S. Almeida, Edgar J. Paredes-Gamero, João B. Pesquero & Ronaldo C. Araújo

  2. Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo, São Paulo, Brazil

    Gabriel R. Estrela, Frederick Wasinski & Danilo C. Almeida

  3. Instituto de Ciências Biomédicas, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil

    Mariane T. Amano, Angela Castoldi & Niels O. S. Câmara

  4. Departamento de Clinica Médica, Universidade de São Paulo, São Paulo, Brazil

    Denise M. A. C. Malheiros

  5. Departamento de Nutrição, Escola de Nutrição, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil

    Carlos C. Barros

  6. Department of Biophysics, Federal University of São Paulo, Rua Botucatu, 862, 7° andar, 04023-062, São Paulo, São Paulo, Brazil

    Ronaldo C. Araújo

Authors
  1. Gabriel R. Estrela
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  2. Frederick Wasinski
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  3. Danilo C. Almeida
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  4. Mariane T. Amano
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  5. Angela Castoldi
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  6. Carolina C. Dias
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  7. Denise M. A. C. Malheiros
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  8. Sandro S. Almeida
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  9. Edgar J. Paredes-Gamero
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  10. João B. Pesquero
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  11. Carlos C. Barros
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  12. Niels O. S. Câmara
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  13. Ronaldo C. Araújo
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Corresponding author

Correspondence to Ronaldo C. Araújo.

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Figure 10

Cisplatin and hepatotoxicity. Hepatotoxicity after 96 h of cisplatin administration evaluated by serum levels of AST (a) and ALT (b). *p < 0.05 compared to the control. Bars = mean and s.e.m. (JPEG 165 kb)

Figure 11

Cisplatin induced alterations in peripheral blood. Ninety-six hours after cisplatin administration, levels of leukocytes (a), neutrophils (b), lymphocytes (c) and monocytes (d). *p < 0.05 compared to the control. Bars = mean and s.e.m. (JPEG 914 kb)

Figure 12

Cisplatin inducing bone marrow supression. Four days after cisplatin administration, bone marrow cells were analyzed for monocytic cells (a), myeloid cells (b), hematopoietic stem cells (c) and progenitor cells (d) in bone marrow *p < 0.05 compared to the control, #p < 0.05 compared to CIS. Bars = mean and s.e.m. (JPEG 951 kb)

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Estrela, G.R., Wasinski, F., Almeida, D.C. et al. Kinin B1 receptor deficiency attenuates cisplatin-induced acute kidney injury by modulating immune cell migration. J Mol Med 92, 399–409 (2014). https://doi.org/10.1007/s00109-013-1116-z

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  • DOI: https://doi.org/10.1007/s00109-013-1116-z

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