Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

Abstract

Abstract-Perturbations of proper functions of the endoplasmic reticulum (ER) cause accumulation of misfolded or unfolded proteins in the cell, creating a condition known as ER stress. Prolonged ER stress has been implicated in hypertension. Oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside, plays a pivotal role in neurogenic hypertension. This study aimed to evaluate the contribution of ER stress in RVLM to oxidative stress-associated hypertension and delineate the underlying molecular mechanisms. The expression of glucose-regulated protein 78 kDa and the phosphorylation of protein kinase RNA-like ER kinase-translation initiation factor α, 2 major protein markers of ER stress, were augmented in RVLM and preceded the development of hypertensive phenotype in spontaneously hypertensive rats. In RVLM of spontaneously hypertensive rats, stabilizing ER stress by salubrinal promoted antihypertension, and scavenging the reactive oxygen species by tempol reduced the augmented ER stress. Furthermore, induction of oxidative stress by angiotensin II induced ER stress in RVLM, and induction of ER stress by tunicamycin in RVLM induced pressor response in normotensive Wistar-Kyoto rats. Autophagy, as reflected by the expression of lysosome-associated membrane protein-2 and microtubule-associated protein 1 light chain 3-II (LC3-II), was significantly increased in RVLM of spontaneously hypertensive rats and was abrogated by salubrinal. In addition, inhibition of autophagy or silencing LC3-II gene in RVLM resulted in antihypertension in spontaneously hypertensive rats. These results suggest that redox-sensitive induction of ER stress and activation of autophagy in RVLM contribute to oxidative stress-

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…rats given Ang II and treated with either tauroursodeoxycholic acid (TUDCA) or PBA led to a 20 mm Hg decrease in blood pressure with either inhibitor, compared with Ang II treatment alone. 55 The Ang II-treated rats receiving either TUDCA or PBA had normalized levels of serum creatinine, a characteristic of impaired renal function, suggesting an attenuation of renal dysfunction in these rats. 56 In our study, both UDCA and 4-PBA improved renal dysfunction and decreased blood pressure after treatment for 8 weeks.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…In addition, Western blot analysis revealed decreased levels of p-AMPK, and elevated levels of p-eIF2α, ATF3, ATF6, XBP1 and cyclooxygenase 2 (COX-2) in SHR carotid arteries. Chao et al [121] found that ERS promoted oxidative stress associated with hypertension in the rostral ventrolateral medulla (RVLM) by increasing the expression of GRP78 and p-eIF2α. ERS also promoted vasoconstriction.…”

“…Salubrinal currently has a new therapeutic value. Chao et al [121] reported that in the RVLM of spontaneously hypertensive rats, salubrinal-mediated ERS stability relieved hypertension. Furthermore, induction of oxidative stress by Ang II induced ERS in the RVLM; induction of ERS by tunicamycin in the RVLM induced the pressor response in normotensive Wistar-Kyoto rats.…”

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

“…ER stress has previously been implicated in hypertension (7,37). To determine whether brain ER stress contributes to DOCA-salt hypertension, and whether ACE2 blunts DOCA-salt hypertension through prevention of ER stress, we measured ER stress marker mRNA and protein levels in the SFO and PVN regions.…”

“…ER stress has been implicated in neurodegenerative diseases, cancer, obesity, and diabetes (13). Very recently, ER stress has been suggested in the development and maintenance of neurogenic hypertension (7,37). However, the mechanisms involved remain to be determined.…”