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J. Biol. Chem., Vol. 279, Issue 41, 43157-43167, October 8, 2004

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Osmotic Diuretics Induce Adenosine A₁ Receptor Expression and Protect Renal Proximal Tubular Epithelial Cells against Cisplatin-mediated Apoptosis^*

Sandeep C. Pingle, Snigdha Mishra¶, Adriana Marcuzzi, Satyanarayan G. Bhat, Yuko Sekino||, Leonard P. Rybak, and Vickram Ramkumar**

From the Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, the ^¶Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, and the ^||Department of Neurobiology and Behavior, Gunma University School of Medicine, Maebashi 371-8511, Japan

Osmotic diuretics are used successfully to alleviate acute tubular necrosis (ATN) produced by chemotherapeutic agents and aminoglycoside antibiotics. The beneficial action of these agents likely involves rapid elimination of the nephrotoxic agents from the kidney by promoting diuresis. Adenosine A₁ receptor (A₁AR) subtype present on renal proximal tubular epithelial and cortical collecting duct cells mediates the antidiuretic and cytoprotective actions of adenosine. These receptors are induced by activation of nuclear factor (NF)-B, a transcription factor reported to mediate hyperosmotic stress-induced cytoprotection in renal medullary cells. In this study, we tested the hypothesis that induction of the A₁AR in renal proximal tubular cells by NF-B contributes to the cytoprotection afforded by osmotic diuretics. Exposure of porcine renal proximal tubular epithelial (LLC-PK₁) cells to mannitol or NaCl produced a significant increase in A₁AR. This increase was preceded by adenosine release and NF-B activation. Expression of an IB- mutant, which acts as a superrepressor of NF-B, abrogated the increase in A₁AR. Cells exposed to mannitol demonstrated increased reactive oxygen species (ROS) generation, which was attenuated by inhibiting xanthine oxidase with allopurinol. Allopurinol attenuated both the increase in A₁AR expression and NF-B activation produced by osmotic diuretics, indicating a role of adenosine metabolites in these processes. Treatment of LLC-PK₁ cells with cisplatin (8 µM) resulted in apoptosis, which was attenuated by mannitol but exacerbated by selective A₁AR blockade. Administration of mannitol to mice increases A₁AR expression and activation of NF-B in renal cortical sections. Taken together, these data provide novel mechanisms of nephroprotection by osmotic diuretics, involving both activation and induction of the A₁AR, the latter mediated through activation of a xanthine oxidase pathway leading to ROS generation and promoting activation of NF-B.

Received for publication, May 20, 2004 , and in revised form, July 20, 2004.

^* This study was funded by National Institutes of Health Grants HL56316-01 (to V. R.) and DC-02396 (to L. P. R.) and by funds from the Central Research Committee, Southern Illinois University School of Medicine (to V. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to the completion of this research.

^** To whom correspondence should be addressed: SIU School of Medicine, Box 19230, Springfield, IL 62974-1222. Tel.: 217-785-2171; Fax: 217-545-0145; E-mail: vramkumar{at}siumed.edu.

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