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

Sci Rep. 2016 Jun 7:6:27112. doi: 10.1038/srep27112.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / physiopathology
  • Animals
  • Apoptosis
  • Cathepsin D / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Folic Acid / adverse effects
  • Humans
  • Kidney Function Tests
  • Kidney Tubules / cytology*
  • Kidney Tubules / drug effects
  • Kidney Tubules / enzymology
  • Male
  • Mice
  • Nephrosis / chemically induced
  • Nephrosis / complications*
  • Nephrosis / drug therapy
  • Nephrosis / enzymology
  • Pepstatins / administration & dosage
  • Pepstatins / pharmacology
  • Reperfusion Injury / complications*
  • Reperfusion Injury / drug therapy
  • Up-Regulation

Substances

  • Pepstatins
  • Folic Acid
  • CTSD protein, human
  • Cathepsin D
  • pepstatin