Activation of A kinase attenuates cisplatin-induced renal tubular cell injury by inhibiting the induction of TNF-α

The role of cyclic AMP/A kinase in cisplatin-induced nephrotoxicity was investigated. A transient exposure (1 -hr) of a porcine renal tubular cell line LLC-PK1 cells to cisplatin caused a delayed injury 6 hr thereafter. Both the mRNA expression for TNF-a and its content were markedly elevated after...

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Published in:Journal of Pharmacological Sciences 2004, Vol.94 (suppl.3), p.263-263
Main Authors: Yuki Shino, Takahisa Yano, Toshio Kubota, Toshiaki Sendo, Yoshinori Itoh, Ryozo Oishi
Format: Article
Language:Japanese
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Summary:The role of cyclic AMP/A kinase in cisplatin-induced nephrotoxicity was investigated. A transient exposure (1 -hr) of a porcine renal tubular cell line LLC-PK1 cells to cisplatin caused a delayed injury 6 hr thereafter. Both the mRNA expression for TNF-a and its content were markedly elevated after exposure to cisplatin. Dibutyryl cyclic AMP (DBcAMP) attenuated the cisplatin-induced cell injury as well as the increase in mRNA for TNF-a and its content, both of which were reversed by an A kinase inhibitor H89. A prostacyclin analog beraprost increased cellular cAMP content in the presence of phosphodiesterase inhibitors and attenuated cisplatin-induced cell injury. The phosphorylation of cyclic AMP responsive element binding protein (CREB) was enhanced after exposure to DBcAMP or beraprost. These findings suggest that activation of A kinase protects renal tubular cells against cisplatin nephrotoxicity by stimulating the CREB phosphorylation and subsequent inhibition of TNF-u induction.
ISSN:1347-8613