Differential Activation of Signaling Pathways Involved in Cell Death, Survival and Inflammation by Radiocontrast Media in Human Renal Proximal Tubular Cells

Abstract

Radiocontrast media (RCM) are widely used in clinical medicine but may lead to radiocontrast-induced nephropathy (RCIN). The pathogenesis of acute renal failure secondary to RCM is not fully understood, but direct toxic effects are believed to be a major cause of RCIN. We have investigated the effect of different types of RCM on signaling pathways known to play a role in cell death, survival, and inflammation. HK-2 cells were incubated with sodium diatrizoate and iomeprol (IOM) at a concentration of 75 mg I/ml for 2 h. Both RCM caused an increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) (p38) and c-Jun N-terminal kinases (JNKs) and NF-κB (at Ser 276), with sodium diatrizoate having a more drastic effect. Although cell viability was reduced significantly by both RCM, in cells pretreated with IOM the cell viability recovered over a 22-h time period after removal of the RCM. However, viability of diatrizoate-treated cells rose at 5 h but then fell at 22 h after removal of the RCM. The decrease in cell viability in diatrizoate-treated cells corresponded with an increase in phosphorylation of JNKs, p38, and NF-κB and a decrease in phosphorylation of Akt, signal transducer and activator of transcription 3, and forkhead box O3a, as well as poly (ADP-ribose) polymerase and caspase-3 cleavage. The recovery in viability of IOM-treated cells corresponded most notably with an increase in STAT3 phosphorylation and induction of Pim-1 kinase. There was also an increase in interleukin-8 release by diatrizoate-treated cells indicating the possibility of proinflammatory effects of RCM. A knowledge of the signaling pathways by which RCM exert their cytotoxic actions may help in finding future therapies for RCIN.

Tetramethylpyrazine Prevents Contrast-Induced Nephropathy by Inhibiting p38 MAPK and FoxO1 Signaling Pathways

“…Our previous work has suggested that CM-induced apoptosis can be mediated by activation of the p38 mitogen-activated protein kinase (MAPK)/inducible nitric oxide synthase (iNOS) signal pathway in vitro [3]. These findings are in excellent agreement with Michele's study in human renal tubular cell line (HK2) and Quintavalle's study in cultured renal tubular cells from CIN patients [12,13]. However, whether p38 MAPK signal also plays a role in vivo and by which nuclear transcription factors p38 MAPK regulates apoptosis have not been investigated.…”

Limb ischemic preconditioning protects against contrast-induced acute kidney injury in rats via phosphorylation of GSK-3β

“…NF-κB activation, which drives a well-known inflammatory process, has also been proposed as a major mechanism involved in CI-AKI [51]. Accordingly, reducing the level of inflammation by suppressing the activation of NF-κB was shown to attenuate CI-AKI [52,53].…”

Remote Ischemic Pre-Conditioning Alleviates ContrastInduced Acute Kidney Injury in Patients With Moderate Chronic Kidney Disease

“…48 The anti-inflammatory effect of RIPC, however, remains controversial. Konstantinov et al showed that RIPC suppressed the expression of pro-inflammatory genes in circulating leukocytes in humans.…”