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Am J Physiol Renal Physiol (December 19, 2007). doi:10.1152/ajprenal.00487.2007
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Submitted on October 19, 2007
Accepted on December 13, 2007

Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells

Istvan Arany1*, Johann Herbert2, Zsolt Herbert3, and Robert L. Safirstein4

1 Pediatrics, UMC, United States
2 Internal medicine, Univ. Kentucky, Lexington, Kentucky, United States
3 Internal Medicine, Univ. Kentucky, Lexington, Kentucky, United States
4 Internal Medicine, UAMS, Little Rock, Arkansas, United States

* To whom correspondence should be addressed. E-mail: iarany{at}ped.umsmed.edu.

We have shown that mouse proximal tubule cells (TKPTS) survive H2O2 stress by activating CREB-mediated transcription via the canonical EGFR/Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor Trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.




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