Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage.
OBJECTIVE
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 SB203580, a p38 MAPKs inhibitor, on oxidative stress, on the oxidation-associated signal, p38 MAPK and on apoptosis in CP-injected rats, starting after the beginning of the renal damage.


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.


RESULTS
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 SB203580.


CONCLUSIONS
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.
Francescato
Heloísa D C
HD
Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Costa
Roberto S
RS
da Silva
Cleonice G A
CG
Coimbra
Terezila M
TM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002945:Cisplatin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002945:Cisplatin