Decreased contraction induced by endothelium-derived contracting factor in prolonged treatment of rat renal artery with endoplasmic reticulum stress inducer

Abstract

Recent evidence suggests that endoplasmic reticulum (ER) stress is involved in the regulation of various physiological functions, including those of the vascular system. However, the relationship between ER stress and vascular function is poorly understood. The endothelial cells control the vascular tone by releasing endothelium-derived relaxing factors and contracting factors (EDCFs). We hypothesized that tunicamycin, an inducer of ER stress, modifies endothelium-dependent contraction and prostaglandins (PGs), a major class of EDCFs, induced contractions in the rat renal artery in rats. An organ-culture technique was used to purely investigate the effects of ER stress on the vascular tissue. We observed that tunicamycin treatment (20μg/mL for 23 ± 1h) did not affect acetylcholine (ACh)-induced relaxation and decreased EDCF-mediated contractions under nitric oxide synthase (NOS) inhibition induced by ACh, ATP, or A23187 (a calcium ionophore) in the renal arteries. Under NOS inhibition, U46619 (a thromboxane A2 mimetic)- and beraprost (a prostacyclin analog)-induced contractions were also decreased in the renal arteries of the tunicamycin-treated group (vs. vehicle), while PGE2- and PGF2α-induced contractions were similar between the groups. Tunicamycin treatment slightly enhanced the contractions induced by phenylephrine, an α1 adrenoceptor ligand. Isotonic high-K+-induced contractions were similar between the vehicle- and tunicamycin-treated groups. Another ER stress inducer, thapsigargin (4μmol/L for 23 ± 1h), also caused substantial reduction of ACh-induced EDCF-mediated contraction (vs. vehicle-treated group). In the cultured renal arteries, tunicamycin and thapsigargin increased the expression of binding immunoglobulin protein (BiP), an ER stress marker. In conclusion, ER stress induction directly affects renal arterial function, especially in reducing EDCF-mediated contractions.