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Evidence that Vascular Endothelial Derived Endothelin‐1 Promotes Development of Tunicamycin‐Induced Endoplasmic Reticulum Stress in Renal Vessels
Author(s) -
De Miguel Carmen,
Rodriguez Marco Antonio,
Pollock David,
Pollock Jennifer
Publication year - 2015
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.29.1_supplement.811.15
Subject(s) - tunicamycin , endoplasmic reticulum , endothelin 1 , unfolded protein response , medicine , endothelin receptor , microbiology and biotechnology , biology , receptor
Levels of the vasoconstrictor peptide endothelin‐1 (ET‐1) are elevated in cardiovascular disease. Endoplasmic reticulum (ER) stress is one of the known mechanisms for cellular apoptosis. Our group has recently implicated the ET‐1 system in the activation of renal ER stress pathways, although it is unclear which cells are involved. To clarify the role of ET‐1 in the development of renal vascular ER stress, we hypothesized that lack of ET‐1 in endothelial cells attenuates tunicamycin (TM)‐induced ER stress in renal vessels. Female mice lacking ET‐1 in vascular endothelial cells (VEET KO) and the corresponding flox controls (n=5‐9/group) received a single i.p. injection of either TM (1.5 mg/kg) or saline. 24 hours post‐injection, renal vessels were isolated, ER stress genes determined by qRT‐PCR, and renal apoptosis detected by TUNEL staining. TM significantly increased the expression of ER stress markers in renal vessels from flox mice (saline vs. TM, fold change/flox+saline, p<0.05; GRP94: 1.0±0.3 vs. 16.5±6.6, ATF‐6: 1.0±0.5 vs. 6.8±3.5, and CHOP: 1.4±0.4 vs. 12.5±1.9). TM treatment led to increased outer medullary, non‐vascular TUNEL staining in flox mice as well. TM failed to increase renal vascular ER stress markers or renal apoptosis in VEET KO mice. These results indicate that ET‐1 is critical for the development of renal vascular ER stress and apoptosis in response to TM, and highlight the possibility of targeting the ET‐1 system as a therapeutic approach against ER stress‐induced renal vascular damage. Funded by NIH T32 DK007545 to CDM and P01 HL95499 to DMP and JSP.