期刊
TOXICOLOGICAL SCIENCES
卷 114, 期 2, 页码 295-301出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfq006
关键词
contrast medium; ER stress; unfolded protein response; apoptosis
类别
资金
- National Science Council [NSC91-2314-B-002-248]
- Department of Health, Executive Yuan of Taiwan [DOH96-TD-F-113-023]
- I-Shou University [97-EDN12]
- National Taiwan University Hospital [NTUH 98-N-1243]
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 2 alpha (eIF2 alpha). Salubrinal, a selective inhibitor of eIF2 alpha 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/eIF2 alpha-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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