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

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 zVAD-fmk to provide protection from cisplatin AKI is different from that of Linkermann and his colleagues, who postulated that apoptosis may not play 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 apoptotic-independent 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⁾.