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Radiocontrast media (RCM)-induced nephrotoxicity (CIN) is a major clinical problem accounting for 12% of all hospital-acquired cases of acute kidney injury. The pathophysiology of CIN is not well understood, but direct toxic effects on renal cells have been postulated as contributing to CIN. We have investigated the effect of a white grape ( Vitis vinifera ) juice extract (WGJe) on human renal proximal tubular (HK-2) cells treated with the radiocontrast medium (RCM) sodium diatrizoate. WGJe caused an increase in phosphorylation of the prosurvival kinases Akt and ERK1/2 in HK-2 cells. Treatment of HK-2 cells with 75 mg I/ml sodium diatrizoate for 2.5 h and then further incubation (for 27.5 h) after removal of the RCM caused a drastic decrease in cell viability. However, pre-treatment with WGJe, prior to incubation with diatrizoate, dramatically improved cell viability. Analysis of key signaling molecules by Western blotting showed that diatrizoate caused a drastic decrease in phosphorylation of Akt (Ser473), FOXO1 (Thr24) and FOXO3a (Thr32) during the initial 2.5 h incubation period, and WGJe pre-treatment caused a reversal of these effects. Further analysis by Western blotting of samples from HK-2 cells cultured for longer periods of time (for up to 27.5 h after an initial 2.5 h exposure to diatrizoate with or without WGJe pre-treatment) showed that WGJe pre-treatment caused a negative effect on phosphorylation of p38, NF-κB (Ser276) and pERK1/2 whilst having a positive effect on the phosphorylation of Akt, FOXO1/FOXO3a and maintained levels of Pim-1 kinase. WGJe may alleviate RCM toxicity through modulation of signaling molecules that are known to be involved in cell death and cell survival and its possible beneficial effects should be further investigated. [ABSTRACT FROM AUTHOR]

Abstract: Ischaemia-reperfusion injury is a common occurrence in renal transplantation and may affect the long-term survival of the allograft. Oxidative stress may play a crucial role in this, with reactive oxygen species formed during reperfusion causing direct cellular damage as well as activating pro-inflammatory pathways. A human proximal tubule cell line (HK-2) was subjected to hydrogen peroxide (H2O2) stress that resulted in phosphorylation of c-jun N-terminal kinases (JNKs) and the transcription factor NF-κB at Ser276, both of which have been associated with inflammation. Interleukin (IL)-8 production also increased upon H2O2 stimulation. Pre-incubation of the cells with mycophenolic acid (MPA) resulted in reduced phosphorylation of both JNKs and NF-κB, and reduced IL-8 release in H2O2-stimulated HK-2 cells. MPA also reduced the H2O2-induced phosphorylation of p38 MAP (mitogen-activated protein) kinase, the extracellular-signal regulated kinase 1/2 (ERK1/2), Akt kinase and the transcription factor CREB (cyclic AMP response element binding protein). In rat kidneys subjected to ischaemia-reperfusion, an increase in both pJNK1/2 and pNF-κB was observed, which was reduced in kidneys obtained from mycophenolate mofetil (MMF)-treated rats. These results suggest that MPA may inhibit pro-inflammatory responses in the kidney by inhibiting activation of pro-inflammatory molecules in both the kidney and human renal proximal tubular cells subjected to oxidative stress. [Copyright &y& Elsevier]