Cisplatin up-regulates the adenosine A 1 receptor in the rat kidney

• Published in: European journal of pharmacology Vol. 442; no. 3; pp. 251 - 264
• Main Authors: Bhat, Satyanarayan G, Mishra, Snigdha, Mei, Yun, Nie, Zhongzhen, Whitworth, Craig A, Rybak, Leonard P, Ramkumar, Vickram
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 2002
• Subjects: acute; Anticancer drug; Apoptosis; Nephrotoxicity; Oxidative stress; Renal failure; Oxidative stress; Anticancer drug; Renal failure; Nephrotoxicity; Apoptosis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)01510-8

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-κB (NF-κB). 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.