Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage


Autoria(s): FRANCESCATO, Heloisa D. C.; COSTA, Roberto S.; SILVA, Cleonice G. A. da; COIMBRA, Terezila M.
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

19/10/2012

19/10/2012

2009

Resumo

Aims: Cisplatin (CP) promotes increased production of reactive oxygen species, which can activate p38 mitogen activated protein kinases (p38 MAPKs) leading to apoptosis and increased expression of proinflammatory mediators that intensify the cytotoxic effects of CP. We investigated the effect of the treatment with S13203580, a p38 MAPKs inhibitor, on oxidative stress, on the oxidation-associated signal, p38 MAPK and on apoptosis in U-injected rats, starting after the beginning of the renal damage. Main methods: Rats (n = 21) were injected with CP (5 mg/kg, i.p.) and 3 and 4 days after some of them (n = 8) were treated with SB203580 (0.5 mg/kg, i.p.). Controls (n = 6) received saline (i.p.). Two or five days after saline or CP injections, plasma creatinine, urinary volume, sodium and potassium fractional excretions, blood urea nitrogen and urinary lipid peroxidation were measured. The kidneys were removed for histological, apoptosis, immunohistochemical and Western blot studies. Key findings: CP caused abnormalities in kidney functions and structure associated with raised urinary peroxidation levels and higher number of apoptotic cells in the outer medulla. The immunostaining studies showed increased numbers of macrophages/monocytes and p-p38 MAPKs positive cells in the renal outer medulla. The increase of p-p38 MAPKs expression was confirmed by Western blot analysis. All of these alterations were attenuated by treatment with S13203580. Significance: These data suggest that the beneficial effect of SB203580 on CP-induced renal damage might be related, in part, to the blockade of p38 MAPK activation with reduction of the inflammatory process, oxidative stress and apoptotic cell death. (C) 2009 Elsevier Inc. All rights reserved.

Identificador

LIFE SCIENCES, v.84, n.17-18, p.590-597, 2009

0024-3205

http://producao.usp.br/handle/BDPI/24418

10.1016/j.lfs.2009.02.004

http://dx.doi.org/10.1016/j.lfs.2009.02.004

Idioma(s)

eng

Publicador

PERGAMON-ELSEVIER SCIENCE LTD

Relação

Life Sciences

Direitos

restrictedAccess

Copyright PERGAMON-ELSEVIER SCIENCE LTD

Palavras-Chave #Cisplatin #p38 mitogen activated protein kinases #SB203580 #Acute renal failure #Inflammation #ACTIVATED PROTEIN-KINASE #PROXIMAL TUBULE CELLS #RAT-KIDNEY #LIPID-PEROXIDATION #OXIDATIVE STRESS #TNF-ALPHA #APOPTOSIS #DEATH #HYPERTROPHY #INVOLVEMENT #Medicine, Research & Experimental #Pharmacology & Pharmacy
Tipo

article

proceedings paper

publishedVersion