title: Cyclosporine-induced tubular vacuolization: the role of Bip/Grp78.
abstract: Cyclosporine (CsA) nephrotoxicity shows characteristic tubular vacuolization (TV) which is endoplasmic reticulum (ER) in origin. However, the cellular events of CsA-induced TV and CsA-induced ER remained unclear. The aim of the present study was to study the nature of TV and the correlation to ER stress. Using proximal tubule NRK-52E cells in vitro and an in vivo model of acute CsA nephrotoxicity, we confirmed that CsA-induced TV was ER in origin and potentially reversible. Our results showed that CsA-induced ER stress and involved ER integrated stress response-related proteins (Bip/Grp78, ATF6, IRE1 and CHOP) but not cytoplasmic ER stress-related chaperones (HSP70, HSP40, HSP27, HSP90 and HSP60). Importantly, Bip/Grp78 was overexpressed on the membrane of TV and suppression of Bip/Grp78 blocked TV formation. In addition, suppression of Bip/Grp78-enhanced CsA-induced cell death and CsA-induced TV formation and Bip/Grp78 overexpression had a characteristic striped pattern in the tubulointerstitium. In summary, we demonstrate that CsA-induced TV was a potentially reversible process in which Bip/Grp78 overexpression is essential for TV formation. It is possible that Bip/Grp78 expression and TV formation may be involved in cellular defense mechanism against CsA nephrotoxicity.
authors: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC. chc.ede@msa.hinet.net
authors: Chi-Hung
authors: CH
authors: Cheng
authors: Kuo-Hsiung
authors: KH
authors: Shu
authors: Horng-Rong
authors: HR
authors: Chang
authors: Ming-Chih
authors: MC
authors: Chou
mesh_terms: D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000633:toxicity; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D016572:Cyclosporine; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP