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

Abstract

Acute kidney injury (AKI) is an abrupt reduction in kidney function caused by different pathological processes. It is associated with a significant morbidity and mortality in the acute phase and an increased risk of developing End Stage Renal Disease. 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 strategies to treat AKI. Lysosomal proteases, particularly Cathepsin D (CtsD), play multiple roles in apoptosis however, their role in AKI is still unknown. Here we describe a novel role for CtsD in AKI. CtsD expression was upregulated in damaged tubular cells in nephrotoxic and ischemia reperfusion (IRI) induced AKI. CtsD inhibition using Pepstatin A led to an improvement in kidney function, a reduction in apoptosis and a decrease in tubular cell damage in kidneys with nephrotoxic or IRI induced AKI. Pepstatin A treatment slowed interstitial fibrosis progression following IRI induced AKI. Renal transplant biopsies with acute tubular necrosis demonstrated high levels of CtsD in damaged tubular cells. These results support a role for CtsD in apoptosis during AKI opening new avenues for the treatment of AKI by targeting lysosomal proteases.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

“…Although Pepstatin A can target other aspartyl proteases than CTSD, it is 26,000 times more specific for CTSD (Ki = 0.5 µmol/L) than for its next target renin (Ki = 13000 µmol/L). Pepstatin A has been proved effective in slowing down chronic kidney disease progression [30,32] and fatty liver disease [209] in experimental animal models. Due to the low bioavailability of this peptidic inhibitor, efforts have been made to design Pepstatin A analogues more suitable for the treatment of human diseases [228].…”

Proteomics and Metabolomics for AKI Diagnosis

“…Therefore, specific peptide fragments in urine may serve as a surrogate marker for altered activity of certain proteases in AKI (ie, MMP-9 or cathepsin D). 224,265,266 As shown in Figure 4B, the danger signal sent out by tubular epithelial cells (ie, owing to oxidative and/or fluid shear stress or advanced glycation end product formation), is transduced on the signal transduction level by Toll-like and advanced glycation end product pattern recognition receptors into inflammatory and cell survival responses. 267 Induction of the NF-κB and the NOD…”

Transcriptome Identified lncRNAs Associated with Renal Fibrosis in UUO Rat Model

“…For example, CtsD was upregulated in damaged tubular cells in nephrotoxic and ischemia reperfusion induced acute kidney injury. CtsD inhibition led to an improvement in kidney function, a reduction in apoptosis and a decrease in tubular cell damage in kidneys (Cocchiaro et al, 2016 ). ATF3 was demonstrated interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-κB sites in the IL-6 and IL-12b gene promoters to protect against acute kidney injury (Li et al, 2010 ).…”