Lack of Cathepsin D in the Renal Proximal Tubular Cells Resulted in Increased Sensitivity against Renal Ischemia/Reperfusion Injury.

Chigure Suzuki,Isei Tanida,Takehiko Sunabori,Soichiro Kakuta,Juan Oliva Trejo,Yasuo Uchiyama,Masaki Ohmuraya

doi:10.3390/ijms20071711

Abstract

Cathepsin D is one of the major lysosomal aspartic proteases that is essential for the normal functioning of the autophagy-lysosomal system. In the kidney, cathepsin D is enriched in renal proximal tubular epithelial cells, and its levels increase during acute kidney injury. To investigate how cathepsin D-deficiency impacts renal proximal tubular cells, we employed a conditional knockout CtsDflox/−; Spink3Cre mouse. Immunohistochemical analyses using anti-cathepsin D antibody revealed that cathepsin D was significantly decreased in tubular epithelial cells of the cortico-medullary region, mainly in renal proximal tubular cells of this mouse. Cathepsin D-deficient renal proximal tubular cells showed an increase of microtubule-associated protein light chain 3 (LC3; a marker for autophagosome/autolysosome)-signals and an accumulation of abnormal autophagic structures. Renal ischemia/reperfusion injury resulted in an increase of early kidney injury marker, Kidney injury molecule 1 (Kim-1), in the cathepsin D-deficient renal tubular epithelial cells of the CtsDflox/−; Spink3Cre mouse. Inflammation marker was also increased in the cortico-medullary region of the CtsDflox/−; Spink3Cre mouse. Our results indicated that lack of cathepsin D in the renal tubular epithelial cells led to an increase of sensitivity against ischemia/reperfusion injury.

Highlights

Cathepsin D is a major lysosomal aspartic protease that is responsible for the degradation of proteins and organelles via the autophagy-lysosomal system [1,2]
We show evidence of the importance of cathepsin D in the renal proximal tubular epithelial cells, by characterizing a cytoprotective function following ischemia/reperfusion injury
Lack of cathepsin D resulted in the accumulation of abnormal autophagy-related structures in renal tubular epithelial cells

Summary

Introduction

Cathepsin D is a major lysosomal aspartic protease that is responsible for the degradation of proteins and organelles via the autophagy-lysosomal system [1,2]. Cathepsin D-deficient neurons accumulate abnormal autophagy-related structures and an increase of LC3 (a marker for autophagosome/autolysosome)-signals [4,5,8]. Cathepsin D is significantly expressed in proximal tubular cells. Renal ischemia/ reperfusion is a common cause of acute kidney injury [9]. Proximal tubular epithelial cells of the cortico-medullary region are highly susceptible to acute ischemia [10,11,12,13]. Using a mouse model of renal ischemia/reperfusion injury, it has been shown that cathepsin D is up-regulated in damaged renal proximal tubular epithelial cells [15,16]. Little is known about the contribution of cathepsin D in the renal proximal tubular epithelial cells. To clarify the function of cathepsin D in the renal proximal tubular epithelial cells, we investigated cathepsin D-deficient renal proximal tubular epithelial cells using a CtsDflox/−; Spink3Cre mouse model

Methods

Results

Conclusion