Cisplatin up-regulates the adenosine A(1) receptor in the rat kidney.
Cisplatin, a widely used anticancer drug, produces significant oto- and nephrotoxicity. Previous data from our laboratory, using cultured cell lines, indicated that cisplatin increases the expression of the adenosine A(1) receptor subtype through generation of reactive oxygen species and activation of nuclear factor-kappa B (NF-kappa B). Since the adenosine A(1) receptor plays an important role in normal renal physiology, this study was performed to determine whether cisplatin modulates adenosine A(1) receptor expression in vivo and whether these receptors play a role in the nephrotoxicity. Male Sprague-Dawley rats, treated with cisplatin (8 mg/kg), developed nephrotoxicity within 3 days, as demonstrated by increased serum creatinine and blood urea nitrogen. Cisplatin also produced a significant increase in malondialdehyde, apoptosis and necrosis in the kidney. The above changes were associated with a time-dependent increase in the expression of adenosine A(1) receptor, as determined by radioligand binding assays, Western blotting and immunocytochemistry, and an increase in adenosine A(1) receptor transcripts. Administration of selective and nonselective antagonists of the adenosine A(1) receptor produced either no change or exacerbated the nephrotoxicity produced by cisplatin. These data indicate that cisplatin can regulate the adenosine A(1) receptor in the kidney and suggest a cytoprotective role of this receptor subtype against cisplatin-induced nephrotoxicity.
Bhat
Satyanarayan G
SG
Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 19629, Springfield, IL 62974-1222, USA.
Mishra
Snigdha
S
Mei
Yun
Y
Nie
Zhongzhen
Z
Whitworth
Craig A
CA
Rybak
Leonard P
LP
Ramkumar
Vickram
V
D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000970:Antineoplastic Agents; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D014970:Xanthines; D000628:Aminophylline; D002110:Caffeine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D002945:Cisplatin