Cocchiaro, Pasquale (2016) Lysosomal protease cathepsin D, new driver of apoptosis during acute kidney injury. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Lysosomal protease cathepsin D, new driver of apoptosis during acute kidney injury
Creators:
CreatorsEmail
Cocchiaro, Pasqualecocchiropasquale@libero.it
Date: 2016
Number of Pages: 112
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Veterinaria e Produzioni Animali
Scuola di dottorato: Scienze veterinarie per la produzione e la sanità
Dottorato: Biologia, patologia e igiene ambientale in medicina veterinaria
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Cringoli, Giuseppegiuseppe.cringoli@unina.it
Tutor:
nomeemail
Pavone, Luigi MicheleUNSPECIFIED
Date: 2016
Number of Pages: 112
Uncontrolled Keywords: Acute kidney injury
Settori scientifico-disciplinari del MIUR: Area 07 - Scienze agrarie e veterinarie > VET/03 - Patologia generale e anatomia patologica veterinaria
Date Deposited: 11 Apr 2016 08:34
Last Modified: 28 Apr 2018 01:00
URI: http://www.fedoa.unina.it/id/eprint/10844
DOI: 10.6093/UNINA/FEDOA/10844

Abstract

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.

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