Excessive endoplasmic reticulum stress induces apoptotic cell death in chronic cyclosporine A nephrotoxicity

AIM：To investigate the impact of excessive endoplasmic reticulum stress on apoptotic cell death in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. METHODS：Male Sprague-Dawley rats on a low-salt diet were subcutaneously injected with vehicle (olive oil, 1 mL·kg-1·d-1) or CsA (15 mg/kg) daily for 1 or 4 weeks. Tubulointerstitial fibrosis and apoptotic cell death were estimated by trichrome staining and TUNEL staining. In addition, immunohistochemistry and immunoblotting were used to evaluate the expression of immunoglobulin-binding protein (BiP), eukaryotic initiation factor 2α (eIF2α), growth arrest and DNA damage-inducible protein 153 (GADD153), caspase-12 and caspase-3. RESULTS：The rats treated with CsA for 1 week did not develop tubulointerstitial fibrosis and TUNEL-positive cells, whereas 4-week treatment with CsA induced typical tubulointerstitial fibrosis and increased TUNEL-positive cells. CsA induced a significant increase in BiP and caspase-12 expression peaked at 1 week, and then returned to normal levels at 4 weeks. In contrast, the expression of eIF2α, GADD153 and caspase-3 in CsA-treated rat kidneys were significantly increased in a time-dependent manner. CONCLUSION：Excessive endoplasmic reticulum stress causes apoptotic cell death by depleting molecular chaperones and stimulating the proapoptotic pathway in chronic CsA nephrotoxicity.