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ER Stress‐Induced SREBP‐2 Activation Contributes to Lipid Accumulation in Tubular Nephrotoxicity
Author(s) -
Lhotak Sarka,
Sood Sudesh,
Ingram Alistair,
Austin Richard
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1002.8
Subject(s) - unfolded protein response , tunicamycin , endoplasmic reticulum , sterol regulatory element binding protein , endocrinology , medicine , chemistry , microbiology and biotechnology , nephrotoxicity , thapsigargin , kidney , biology , sterol , cholesterol
Disruption of protein folding in the endoplasmic reticulum (ER) leads to ER stress and activation of the unfolded protein response (UPR). Tubular damage caused by nephrotoxic drugs is associated with ER stress. Since ER stress is known to induce lipid dysregulation through the activation of sterol regulatory element binding proteins (SREBPs), we hypothesized that lipid accumulation observed in proximal tubules affected by nephrotoxic drugs is a consequence of ER stress‐induced SREBP activation. Mice injected with tunicamycin display vacuolization and ER stress in proximal tubules. The vacuoles contain lipids that co‐localize with increased SREBP‐2 expression and markers of ER stress. In kidney biopsies from cyclosporine A (CsA)‐treated patients we show by immunohistochemistry the co‐localization of SREBP‐2 and ER stress markers in the damaged tubules. Treatment of HK2 renal cells with tunicamycin, thapsigargin or CsA caused UPR activation and increased lipid content. SREBP‐2 activation was shown by the enhanced sterol‐regulatory element‐GFP fluorescence, increased mRNA of downstream genes, and the presence of the mature form of SREBP‐2 on Western blot. These outcomes were blocked by AEBSF, an inhibitor of SREBP‐2 processing. We conclude that lipid accumulation in diseased kidney is associated with SREBP‐2 activation by ER stress . Supported by Heart and Stroke Foundation grant NA6024.