This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yano, T. Articles by Oishi, R. Search for Related Content PubMed PubMed Citation Articles by Yano, T. Articles by Oishi, R.

(American Journal of Pathology. 2005;166:1333-1342.)
© 2005 American Society for Investigative Pathology

A Prostacyclin Analog Prevents Radiocontrast Nephropathy via Phosphorylation of Cyclic AMP Response Element Binding Protein

Takahisa Yano^*, Yoshinori Itoh^*, Toshio Kubota^*, Toshiaki Sendo^*, Tatsuya Koyama, Takuya Fujita, Kumiko Saeki, Akira Yuo and Ryozo Oishi^*

From the Department of Pharmacy,^* Kyushu University Hospital, Fukuoka; the Department of Biochemical Pharmacology, Kyoto Pharmaceutical University, Kyoto; and the Department of Hematology, Research Institute, International Medical Center of Japan, Tokyo, Japan

We reported previously that radiocontrast medium induces caspase-dependent apoptosis and that cAMP analogs inhibit cell injury in cultured renal tubular cells. In the present study, cellular me-chanisms underlying the protective effects of cAMP were determined. Ioversol, a radiocontrast medium, caused cell injury accompanied by decreases in Bcl-2, increases in Bax, and caspase activation in LLC-PK1 cells. Both cell injury and cellular events induced by ioversol were inhibited by dibutyryl cAMP and the prostacyclin analog beraprost. Dibutyryl cAMP increased phosphorylation of Akt and CREB, both of which were reversed by H89, wortmannin and the Akt inhibitor SH-6. The protective effect of dibutyryl cAMP was also reversed by these kinase inhibitors. In dominant-negative CREB-transfected cells, dibutyryl cAMP no longer prevented cell injury or inhibited changes in mRNA expression of Bcl-2 and Bax. In mice with unilateral renal occlusion, ioversol increased urinary ex-cretion of N-acetyl-ß-D-glucosaminidase with con-comitant decreases in Bcl-2 mRNA, increases in Bax mRNA, activation of caspase-3, and induction of apoptosis in tubular and interstitial cells. Beraprost completely reversed these in vivo effects of ioversol. These findings suggest that elevation of endogenous cAMP effectively prevents radiocontrast nephropathy through activation of A kinase/PI 3-kinase/Akt followed by CREB phosphorylation and enhanced expression of Bcl-2.

This article has been cited by other articles:

				S.-Y. Kim, M. Seo, Y. Kim, Y.-I. Lee, J.-M. Oh, E.-A. Cho, J.-S. Kang, and Y.-S. Juhnn Stimulatory Heterotrimeric GTP-binding Protein Inhibits Hydrogen Peroxide-induced Apoptosis by Repressing BAK Induction in SH-SY5Y Human Neuroblastoma Cells J. Biol. Chem., January 18, 2008; 283(3): 1350 - 1361. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, M. K. Kuhlmann, S. Kohlbacher, M. Scheer, A. Grgic, M. B. Heckmann, and M. Uder Cytotoxicity of Iodinated and Gadolinium-based Contrast Agents in Renal Tubular Cells at Angiographic Concentrations: In Vitro Study Radiology, December 19, 2006; (2006) 2422060245. [Abstract] [Full Text]

				H. Servais, Y. Jossin, F. Van Bambeke, P. M. Tulkens, and M.-P. Mingeot-Leclercq Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK1 Cells Subjected to Electroporation. Antimicrob. Agents Chemother., April 1, 2006; 50(4): 1213 - 1221. [Abstract] [Full Text] [PDF]