Non-apoptotic effects of antiapoptotic agent zVAD-fmk in renal injury

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To the Editor: We read with interest the paper by Linkermann et al., 1 who demonstrated that specific inhibition of apoptosis by the pan-caspase inhibitor zVAD-fmk was unable to prevent ischemia–reperfusion (IR)-induced kidney damage, renal dysfunction, and cell death. Recently, we also reported that zVAD-fmk did not improve cisplatin-induced decline in renal function, histology, and cell death, but rather worsened renal damage. 2 However, our interpretation of inability of zVADfmk to provide protection from cisplatin acute kidney injury (AKI) is different from that of Linkermann and his colleagues, who postulated that apoptosis may not have much of a role in renal IR injury. Our conclusions are based on several observations. First, we provided evidence that zVAD-fmk promoted lysosomal dysfunction and impaired autophagic flux by blocking autophagosomal clearance that worsened renal function. 2 Second, in renal tubular epithelial cells in culture, we showed that treatment of cells with zVAD-fmk prevented cisplatin-induced apoptosis but promoted defects in autophagic flux, and cells eventually died of necrotic cell death. 2 Third, others have shown zVAD-fmk promotes autophagic and necrotic cell death and is capable of inhibiting lysosomal proteases including cathepsins and calpains in renal and non-renal cells, resulting in lysosomal dysfunction. 3 Therefore, the antiapoptotic effect of zVAD-fmk will be confounded in AKI considering its apoptoticindependent effects. Thus, considering these observations, one should be cautious about concluding that apoptosis is not important in AKI. Such a conclusion would be contrary to numerous studies that have described the role of apoptosis in AKI and that renal function in AKI correlates better with apoptosis than necrosis. 4