MATE-1 modulation by kinin B1 receptor enhances cisplatin efflux from renal cells.
Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.
Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 Andar, 04039-032, São Paulo, SP, Brazil.|Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900, São Paulo, SP, Brazil.
Gabriel R
GR
Estrela
Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 Andar, 04039-032, São Paulo, SP, Brazil.|Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900, São Paulo, SP, Brazil.
Frederick
F
Wasinski
Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900, São Paulo, SP, Brazil.
Raphael J F
RJF
Felizardo
Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany.
Laura L
LL
Souza
Department of Immunology, Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, 05508-900, São Paulo, SP, Brazil.
Niels O S
NOS
Câmara
Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany.
Michael
M
Bader
Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 Andar, 04039-032, São Paulo, SP, Brazil. araujo.ronaldo@unifesp.br.|Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900, São Paulo, SP, Brazil. araujo.ronaldo@unifesp.br.
Ronaldo C
RC
Araujo
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000235:genetics* / Q000378:metabolism
D065169:Bradykinin B1 Receptor Antagonists; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D043783:Receptor, Bradykinin B1; D002945:Cisplatin
Cisplatin nephrotoxicity; Kinins; Organic transporters