The role of endoplasmic reticulum stress-related unfolded protein response in the radiocontrast medium-induced renal tubular cell injury.
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 2alpha (eIF2alpha). Salubrinal, a selective inhibitor of eIF2alpha 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/eIF2alpha-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.
Wu
Cheng T
CT
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Sheu
Meei L
ML
Tsai
Keh S
KS
Weng
Te I
TI
Chiang
Chih K
CK
Liu
Shing H
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D003287:Contrast Media / Q000633:toxicity*; D003974:Diatrizoate Meglumine / Q000633:toxicity*; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011489:Protein Denaturation; D017510:Protein Folding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D015415:Biomarkers; D002934:Cinnamates; D003287:Contrast Media; D003974:Diatrizoate Meglumine; D054736:Elongation Factor 2 Kinase; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D013890:Thiourea; D019892:eIF-2 Kinase; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C053387:endoplasmin; C496827:salubrinal; C517691:Eef2k protein, rat