Premium
Effects of 20‐HETE analogues on intracellular signaling cascades in renal proximal tubular cells
Author(s) -
Akbulut Talha,
Regner Kevin R.,
Roman Richard J.,
Park Frank
Publication year - 2009
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.23.1_supplement.816.5
Subject(s) - p38 mitogen activated protein kinases , apoptosis , chemistry , mapk/erk pathway , kidney , signal transduction , intracellular , medicine , pharmacology , endocrinology , microbiology and biotechnology , biology , biochemistry
We recently demonstrated that the 20‐hydroxyeicosatetraenoic acid (20‐HETE) analogues, 5,14‐20‐HEDE (WIT003) and 5,14‐20‐HEDGE (HEDGE) protect the kidney from ischemia‐reperfusion injury (IRI), and the protection is more pronounced with the HEDGE compound. In the present study, we performed in vitro assays using the LLC‐PK 1 proximal tubular cell line to investigate the signaling cascades that may underlie the renoprotective effect of 20‐HETE analogues. Incubation with 20‐HETE (20 µM) for 60 min resulted in a rapid increase in the activation of the pro‐survival Erk1/2 pathway, including c‐raf (123 +/‐ 1%), MEK1/2 (285 +/‐ 8%), and ERK1/2 (493 +/‐ 36%) as determined by Western blot analysis. Similar increases in the ERK1/2 pathway were also detected using equimolar amounts of HEDGE and WIT003 with WIT003 being more efficacious than 20‐HETE and HEDGE (750% versus 20‐HETE and 500% versus HEDGE, p<0.001). Interestingly, WIT003 also activated the pro‐apoptotic SAPK/JNK (514%, p<0.0001) and p38 MAPK (411%, p=0.0001) pathways. In contrast, 20‐HETE and HEDGE did not activate these pathways. Our results suggest that HEDGE closely mimics the effects of 20‐HETE to selectively activate pro‐survival Erk1/2 pathway in LLC‐PK 1 cells. WIT003, unlike HEDGE and 20‐HETE, also activates pro‐apoptotic pathways and this may explain why it is less effective at protecting the kidney following IRI in vivo .