title: Radiocontrast media cause dephosphorylation of Akt and downstream signaling targets in human renal proximal tubular cells.
abstract: Radiocontrast medium induced nephrotoxicity is a major clinical problem. There is considerable interest in reducing the incidence of acute renal failure due to the use of radiocontrast media (RCM). Reduction of renal blood flow and direct toxic effect on renal tubular epithelial cells have been postulated as major causes of RCM nephropathy. Understanding the molecular mechanisms by which RCM cause cell damage may allow the development of pharmacological therapy to prevent their nephrotoxicity. In this work we have investigated the signaling pathways that may be affected by RCM. The incubation of human renal tubular proximal cells with sodium diatrizoate, iopromide and iomeprol caused a marked dephosphorylation of the kinase Akt on Ser473 within 5min of incubation. RCM also caused a decrease in cell viability, which was substantially alleviated by transfecting the cells with a constitutively active form of Akt. Further downstream targets of Akt, including the Forkhead family of transcription factors FKHR and FKHRL1, were also dephosphorylated by RCM at Thr24 and Thr32, respectively. The P70S6 kinase was also dephosphorylated at Thr389 and Ser371 by RCM. However there was a more dramatic decrease in phosphorylation of the phosphorylated form of mammalian target of rapamycin (mTOR) and of the extracellular-signal regulated kinases (ERK) 1/2 caused by sodium diatrizoate than by iopromide. These results demonstrate the effect of RCM on some intracellular signaling pathways that may allow understanding of the mechanism of their toxicity and may allow the development of strategies to overcome their adverse effects.
authors.affiliation: Cattedra di Nefrologia, Università Magna Graecia di Catanzaro, Viale Europa, loc Germaneto, Catanzaro, Italy. andreucci@unicz.it
authors.forename: Michele
authors.initials: M
authors.lastname: Andreucci
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fuiano
authors.forename: Pierangela
authors.initials: P
authors.lastname: Presta
authors.forename: Pasquale
authors.initials: P
authors.lastname: Esposito
authors.forename: Teresa
authors.initials: T
authors.lastname: Faga
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bisesti
authors.forename: Alfredo
authors.initials: A
authors.lastname: Procino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Altieri
authors.forename: Carmela
authors.initials: C
authors.lastname: Tozzo
authors.forename: Bruno
authors.initials: B
authors.lastname: Memoli
authors.forename: Ashour
authors.initials: A
authors.lastname: Michael
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000009:adverse effects*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D003287:Contrast Media; D051057:Proto-Oncogene Proteins c-akt