Effect of JNK inhibition on cisplatin-induced renal damage.
BACKGROUND
Cisplatin therapy is effective against many tumours, however, the nephrotoxicity of this drug is a dose-limiting factor. Apoptosis and necrosis of tubular cells and inflammatory events contribute to the cisplatin-induced nephrotoxicity. Cisplatin promotes increased production of reactive oxygen species, which can activate c-jun N-terminal kinase (JNK) that is a mediator of apoptosis and can lead to increased expression of proinflammatory mediators that could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect that SP600125, a selective inhibitor of phosphorylated JNK (p-JNK), has on the renal damage caused by cisplatin use.


METHODS
A total of 33 male Wistar rats received SP600125 (15 mg/kg/day, s.c., diluted in polyethylene glycol) for 4 days. At 24 h after the first dose, those 33 rats, plus an additional 30, were injected with cisplatin (5 mg/kg, i.p.). In addition, 18 control rats were injected with saline, and 12 rats with polyethylene glycol. At 2 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium, and the kidneys removed for histological, immunohistochemical and Western blot studies.


RESULTS
Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes), p-JNK, apoptotic cells, and tubular cell necrosis in the renal cortices and outer medullae. The increase of p-JNK expression was also confirmed by Western blot analysis. All of these alterations were attenuated by treatment with SP600125.


CONCLUSIONS
The protective effect of SP600125 on cisplatin-induced renal damage seems to be related to the reduction in the apoptotic cell death and to the restriction of renal inflammation.
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
Júnior
Fernando Barbosa
FB
Coimbra
Terezila M
TM
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D005919:Glomerular Filtration Rate; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced; D015227:Lipid Peroxidation; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D009336:Necrosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000873:Anthracenes; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4; D002945:Cisplatin