Jo Fusakazu, Jo Hiromi, Hilzendeger Aline M, Thompson Anthony P, Cassell Martin D, Rutkowski D Thomas, Davisson Robin L, Grobe Justin L, Sigmund Curt D
From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
Hypertension. 2015 Jun;65(6):1341-8. doi: 10.1161/HYPERTENSIONAHA.115.05377. Epub 2015 Apr 20.
Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein-deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt-induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein-deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt-induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.
内质网应激已成为高血压的一个重要机制。我们研究了内质网应激在介导醋酸脱氧皮质酮（DOCA）-盐诱导的盐摄入量增加和高血压效应中的作用。脑室内注射内质网应激减轻化学伴侣牛磺熊去氧胆酸对高血压程度无影响，但显著降低了DOCA-盐诱导的盐摄入量。牛磺熊去氧胆酸停用后，盐摄入量又恢复增加。脑室内注入另一种化学伴侣4-苯基丁酸后，盐摄入量也降低。在DOCA-盐处理小鼠的穹窿下器和视上核中，不可修复内质网应激标志物CCAAT同源结合蛋白的免疫反应性增加，但在对照小鼠和CCAAT同源结合蛋白缺陷小鼠中未检测到该信号。电子显微镜显示穹窿下器内质网结构异常（膜长度减少、膜肿胀和核糖体数量减少），与内质网应激一致。向穹窿下器靶向递送内质网驻留伴侣蛋白GRP78可降低DOCA-盐诱导的盐摄入量。在CCAAT同源结合蛋白缺陷小鼠中，DOCA-盐诱导的盐摄入量增加受到抑制，但这些小鼠表现出正常的高血压反应。我们得出以下结论：（1）脑内质网应激介导盐摄入量，但不介导对DOCA-盐的血压反应；（2）DOCA-盐导致穹窿下器内质网应激，当被GRP78减弱时可抑制盐摄入量；（3）CCAAT同源结合蛋白可能在DOCA-盐诱导的盐摄入量中发挥功能作用。结果表明内质网应激在介导DOCA-盐对盐摄入量和血压影响方面的重要性存在机制差异。
