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

Reiko Inagi, Masaomi Nangaku, Hiroshi Onogi, Hiroshi Ueyama, Yasuko Kitao, Kiyokazu Nakazato, Satoshi Ogawa, Kiyoshi Kurokawa, William G. Couser, Toshio Miyata

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

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 hi 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.

Original languageEnglish
Pages (from-to)2639-2650
Number of pages12
JournalKidney international
Volume68
Issue number6
DOIs
Publication statusPublished - 2005 Dec
Externally publishedYes

Keywords

  • Megsin
  • Oxygen/glucose- regulated protein (ORP/GRP)
  • Podocyte
  • Protein malfolding
  • Proteinuria
  • Serpin

ASJC Scopus subject areas

  • Nephrology

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