Cyclosporine-Induced Tubular Vacuolization: The Role of Bip/Grp78

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.