The Role of Endoplasmic Reticulum Stress–Related Unfolded Protein Response in the Radiocontrast Medium–Induced Renal Tubular Cell Injury

• Published in: Toxicological sciences 2010-04, Vol.114 (2), p.295-301
• Main Authors: Wu, Cheng T., Sheu, Meei L., Tsai, Keh S., Weng, Te I., Chiang, Chih K., Liu, Shing H.
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Biomarkers - metabolism; Cell Line; Cell Survival - drug effects; Cinnamates - pharmacology; Contrast Media - toxicity; contrast medium; Diatrizoate Meglumine - toxicity; eIF-2 Kinase - metabolism; Elongation Factor 2 Kinase - metabolism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; ER stress; Gene Silencing; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Phosphorylation - drug effects; Protein Denaturation; Protein Folding - drug effects; Rats; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Thiourea - analogs & derivatives; Thiourea - pharmacology; unfolded protein response; Unfolded Protein Response - drug effects
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfq006

Contrast medium (CM) induces a direct toxic effect on renal tubular cells. This toxic effect may have a role in the pathophysiology of CM-induced nephropathy. CM has been shown to affect the endoplasmic reticulum (ER)–related capacity. Unfolded protein response (UPR) is known as a prosurvival response to reduce the accumulation of unfolded proteins and restore normal ER function. However, the role of ER stress–related UPR in the CM-induced renal cell injury still remains unclear. In this study, we examined whether UPR participates in urografin (an ionic CM)-induced renal tubular cells apoptosis. Treatment with urografin in normal rat renal tubular cell line (NRK52E) markedly increased cell apoptosis and decreased cell viability with a dose- and time-dependent manner. The cell necrosis was not increased in urografin-treated cells. Urografin also enhance the induction of ER stress–related markers in NRK52E cells, including glucose-regulated protein (GRP)78 and GRP94 expressions, procaspase-12 cleavage, phosphorylation of PERK (PKR [double-stranded RNA–activated protein kinase]-like ER kinase), and eukaryotic initiation factor 2α (eIF2α). Salubrinal, a selective inhibitor of eIF2α dephosphorylation, effectively decreased urografin-induced cell apoptosis. Furthermore, transfection of GRP78-small interfering RNA in NRK52E cells significantly enhanced urografin-induced cell apoptosis. These results suggest that GRP78/eIF2α-related signals play a protective role during UPR, and the activation of ER stress–related UPR may play an important regulative role in urografin-induced renal tubular injury.