Radiocontrast media cause dephosphorylation of Akt and downstream signaling targets in human renal proximal tubular cells.
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.
Andreucci
Michele
M
Cattedra di Nefrologia, Università Magna Graecia di Catanzaro, Viale Europa, loc Germaneto, Catanzaro, Italy. andreucci@unicz.it
Fuiano
Giorgio
G
Presta
Pierangela
P
Esposito
Pasquale
P
Faga
Teresa
T
Bisesti
Vincenzo
V
Procino
Alfredo
A
Altieri
Vincenzo
V
Tozzo
Carmela
C
Memoli
Bruno
B
Michael
Ashour
A
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
D003287:Contrast Media; D051057:Proto-Oncogene Proteins c-akt