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Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats
Author(s) -
Xie YanHua,
Wang SiWang,
Zhang Yaping,
Edvinsson Lars,
Xu CangBao
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12123
Subject(s) - endocrinology , medicine , contractility , endothelin receptor , myograph , receptor , agonist , biology , endothelin 1 , kidney , contraction (grammar)
Increased renal artery contractility leads to renal vasospasm and ischaemia as well as kidney damage. This study was designed to examine the hypothesis that organ culture of renal arteries induces transcriptional up‐regulation of endothelin type A ( ET A ) and type B 2 ( ET B2 ) receptors in the smooth muscle cells via activation of nuclear factor‐kappa B ( NF ‐κ B ) and subsequently increases renal artery contractility. Rat renal artery segments were organ‐cultured for 6 or 24 hr to increase endothelin receptor‐mediated contraction. To dissect molecular mechanisms involved in this process, inhibitors for NF ‐κ B signalling pathway ( MG ‐132 and BMS 345541), transcription (actinomycin D ) and translation (cycloheximide) were used during organ culture. Endothelin receptors were studied using a sensitive myograph (functional contractility), real‐time PCR ( mRNA analysis) and immunohistochemistry (protein localization). Compared with fresh segments, contractile responses to endothelin‐1 (non‐selective endothelin receptor agonist) and sarafotoxin 6c (selective ET B receptor agonist) were significantly increased in the segments after 24 hr of organ culture; ET B2 receptor‐mediated maximal contraction increased from 2.7 ± 0.5 to 135.3 ± 5.1 ( p < 0.001), and potency ( pEC 50 ) of ET A receptor agonist increased from 8.20 ± 0.04 to 8.72 ± 0.07 ( p < 0.001). This was in parallel with increased corresponding mRNA and protein expression for ET A and ET B2 receptors. BMS 345541, MG ‐132, actinomycin D or cyclohexamide, respectively, suppressed the up‐regulation of ET A and ET B2 receptors. Immunostaining performed with specific antibody showed that I κ B was phosphorylated during organ culture. In conclusion, activation of NF ‐κ B mediates up‐regulation of ET A and ET B2 receptors and subsequently increases renal artery contractility, which may contribute to renal vasospasm and ischaemia as well as kidney damage.