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

Cheng T. Wu; Meei L. Sheu; Keh S. Tsai; Te I. Weng; Chih K. Chiang; Shing H. Liu
April 2010
Toxicological Sciences;Apr2010, Vol. 114 Issue 2, p295
Academic Journal
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.


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