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Molecular Mechanisms of All‐ Trans ‐Retinoic Acid Mediated Cytoprotection Against Renal Cell Injury
Author(s) -
Sapiro Jessica M,
Burrell Katherine L,
Lau Serrine S
Publication year - 2016
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.30.1_supplement.711.4
Subject(s) - cytoprotection , mapk/erk pathway , protein kinase b , chemistry , kinase , retinoic acid , pharmacology , oxidative stress , microbiology and biotechnology , biology , biochemistry , signal transduction , gene
One of the major etiologies of acute kidney injury is chemical‐induced nephrotoxicity. Pretreatment of LLC‐PK 1 cells with all‐ trans ‐retinoic acid (ATRA, 25 μM, 24 hr) affords cytoprotection against p ‐aminophenol (PAP), and 2‐(glutathion‐ S ‐yl)hydroquinone‐induced necrosis. In contrast co‐treatment of toxicant with ATRA does not afford cytoprotection, suggesting that ATRA modulates critical signaling pathways prior to toxicant exposure. Interestingly, ATRA did not alter PAP‐induced ROS generation and had a modest effect on Nrf2 induction suggesting other stress response proteins beyond ROS reduction contribute to ATRA protection. Therefore, additional protecting mechanisms were examined. During ATRA‐mediated pretreatment, the ER stress proteins Grp78 and p ‐eIF2α increased 2‐fold in a time‐dependent manner (ATRA 24 hr and 4 hr, respectively). Furthermore, ATRA increased expression of the cellular stress kinases p ‐ERK and p ‐AKT with maximum levels at 30 min. p ‐ERK decreased to basal levels after 4 hr, while p ‐AKT remained elevated for 24 hr, coinciding with the time required for maximal ATRA cytoprotection. Moreover, induction of these stress kinases was observed at concentrations of ATRA (10 and 25 μM) required for cytoprotection. Interestingly, the p ‐ERK inhibitor PD98059 reduced ATRA protection against PAP toxicity indicating a possible function of p ‐ERK and its downstream target genes in the ATRA mechanism for protection. We further determined that ATRA led to a prompt increase in cyclin D1 levels (1–4 hr, 3‐fold). Collectively, UPR proteins (Grp78, p ‐eIF2α), stress kinases ( p ‐AKT, p ‐ERK) and mitogenic effects (cyclin D1) function interdependently to afford ATRA protection against renal cell damage Support or Funding Information ES006694, T32ES007091, ES016578, ASPET‐SURF