Ischemic preconditioning attenuates ischemia/reperfusion‐induced acute kidney injury dependent on mitochondrial protease <scp>CLPP</scp>

Ischemic preconditioning (IPC) is a phenomenon in which brief periods of ischemia trigger protective mechanisms that alleviate subsequent ischemia-reperfusion injury (IRI), although the precise protective mechanism remains unclear. This study investigated the mechanism by which IPC protects acute kidney injury (AKI) induced by renal IRI. We found that IPC for 10 min significantly ameliorated IRI-induced AKI, whereas IPC for 5 or 15 min did not have any protective effects. Renal ischemia increased the expression of caseinolytic protease P (CLPP) in tubular epithelial cells. The peak effect was reached after 10 min of renal ischemia, during which no mitochondrial deposition of misfolded/unfolded proteins or signs of AKI were evident. However, after 15 min of renal ischemia, there was no further increase in CLPP levels, which was accompanied by mitochondrial deposition of misfolded/unfolded proteins and signs of AKI. The increase in CLPP levels suggests potential activation of the mitochondrial unfolded protein response (UPR^mt), which is a cellular stress response pathway that regulates the expression of mitochondrial chaperones and proteases to maintain protein homeostasis within the mitochondria. Knockdown of Clpp led to the aggregation of mitochondrial unfolded/misfolded proteins and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which indicated integrated stress response (ISR) activation. Clpp knockdown in mice antagonized the protective effects induced by IPC for 10 min during renal IRI. Furthermore, the inhibition of ISR activation by an ISR inhibitor (ISRIB) may also impede the protective effects of IPC for 10 min. This study indicates that IPC can ameliorate renal IRI injury and that its effect is dependent on CLPP.