Lysosomal protease cathepsin D, new driver of apoptosis during acute kidney injury

Acute kidney injury (AKI) is an abrupt reduction in kidney function due to tubular cell death by toxic or ischemic (IRI) insults. It significantly contributes to graft loss as 20-80% of deceased donor kidneys suffer IRI induced AKI. Despite the progress in the management of the disease, mortality rates in the last five decades remain unchanged at around 50%. Therefore there is an urgent need to find new therapeutic targets against AKI. Lysosomal proteases, particularly CtsD, can play multiple roles in apoptosis, however its role during AKI is still unknown. Here I describe a novel role for CtsD in AKI. CtsD was upregulated in damage tubular cells in nephrotoxic and ischemic (IRI) induced AKI. CtsD pharmacological inhibition using Pepstatin A lead to an improvement in kidney function, a reduction in apoptosis and an overall decrease in the number of damaged tubular cells in the kidneys with nephrotoxic or IRI induced AKI. Treatment with Pepstatin A slowed progression to CKD from IRI induced AKI, with a reduction in interstitial fibrosis. Analysis of acute tubular necrosis (ATN) transplanted patient biopsies revealed high levels of CtsD in damaged looking tubular cells. CtsD needs to be translocated from the lysosomes into the cytosol to exert its pro-apoptotic function. In agreement with this, CtsD distribution in human disease differed from non-apoptotic to apoptotic cells, with a lysosomal or cytosolic distribution respectively. My work support the role of CtsD in apoptosis during AKI opening new prospects for the treatment of AKI by targeting lysosomal proteases.