Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation.

Abstract:

BACKGROUND:An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, such as oxygen-regulated proteins 150 (ORP150) and glucose-regulated proteins (GRPs). While ER stress is important in various diseases, a pathophysiologic role for ER stress in kidney disease remains elusive. Here we investigate expression of ER stress proteins in cultured rat podocytes as well as in our recently developed animal model of abnormal protein retention within the ER of podocytes (i.e., megsin transgenic rat). METHODS:The expression of ER stress inducible proteins (ORP150, GRP78, or GRP94) in cultured podocytes treated with tunicamycin, A23187, SNAP, hypoxia, or hyperglycemia, and the renal tissues or isolated glomeruli from megsin transgenic rats was analyzed by Western blotting analysis, immunohistochemistry, or confocal microscopy. RESULTS:Cultured podocytes demonstrated that treatment with tunicamycin, A23187, and SNAP, but not hypoxia or hyperglycemia, up-regulate expression of ER stress proteins. Extracts of isolated glomeruli from megsin transgenic rats reveal marked up-regulation of ER stress chaperones in podocytes, which was supported by immunohistochemical analysis. Confocal microscopy revealed that ER stress in podocytes was associated with cellular injury. Podocytes of transgenic rats overexpressing a mutant megsin, without the capacity for polymerization within the ER, do not exhibit ER stress or podocyte damage, suggesting a pathogenic role of ER retention of polymerized megsin. CONCLUSION:This paper implicates a crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury.

journal_name

Kidney Int

journal_title

Kidney international

authors

Inagi R,Nangaku M,Onogi H,Ueyama H,Kitao Y,Nakazato K,Ogawa S,Kurokawa K,Couser WG,Miyata T

doi

10.1111/j.1523-1755.2005.00736.x

subject

Has Abstract

pub_date

2005-12-01 00:00:00

pages

2639-50

issue

6

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(15)51172-1

journal_volume

68

pub_type

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