Dataset Information

In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension.

ABSTRACT: Renovascular hypertension in mice is characterized by an elevation in hypothalamic angiotensin II levels. The paraventricular nucleus (PVN) is a major cardioregulatory site implicated in the neurogenic component of renovascular hypertension. Increased superoxide (O(2)(-·)) production in the PVN is involved in angiotensin II-dependent neurocardiovascular diseases such as hypertension and heart failure. Here, we tested the hypothesis that excessive O(2)(-·) production and activation of the redox-regulated transcription factor activator protein-1 (AP-1) in PVN contributes to the development and maintenance of renovascular hypertension. Male C57BL/6 mice underwent implantation of radiotelemeters, bilateral PVN injections of an adenovirus (Ad) encoding superoxide dismutase (AdCuZnSOD) or a control gene (LacZ), and unilateral renal artery clipping (2-kidney, one-clip [2K1C]) or sham surgery. AP-1 activity was longitudinally monitored in vivo by bioluminescence imaging in 2K1C or sham mice that had undergone PVN-targeted microinjections of an Ad encoding the firefly luciferase (Luc) gene downstream of AP-1 response elements (AdAP-1Luc). 2K1C evoked chronic hypertension and an increase in O(2)(-·) production in the PVN. Viral delivery of CuZnSOD to the PVN not only prevented the elevation in O(2)(-·) but also abolished renovascular hypertension. 2K1C also caused a surge in AP-1 activity in the PVN, which paralleled the rise in O(2)(-·) production in this brain region, and this was prevented by treatment with AdCuZnSOD. Finally, Ad-mediated expression of a dominant-negative inhibitor of AP-1 activity in the PVN prevented 2K1C-evoked hypertension. These results implicate oxidant signaling and AP-1 transcriptional activity in the PVN as key mediators in the pathogenesis of renovascular hypertension.

SUBMITTER: Burmeister MA

PROVIDER: S-EPMC3026319 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension.

Burmeister Melissa A MA Young Colin N CN Braga Valdir A VA Butler Scott D SD Sharma Ram V RV Davisson Robin L RL

Hypertension (Dallas, Tex. : 1979) 20101220 2

Renovascular hypertension in mice is characterized by an elevation in hypothalamic angiotensin II levels. The paraventricular nucleus (PVN) is a major cardioregulatory site implicated in the neurogenic component of renovascular hypertension. Increased superoxide (O(2)(-·)) production in the PVN is involved in angiotensin II-dependent neurocardiovascular diseases such as hypertension and heart failure. Here, we tested the hypothesis that excessive O(2)(-·) production and activation of the redox-r ...[more]

PMID: 21173341

Similar Datasets

Project description:Background: The central nervous system plays a vital role in the development of hypertension, but the molecular regulatory mechanisms are not fully understood. This study aimed to explore signaling in the paraventricular nucleus (PVN) which might contribute to renal hypertension. Methods: Renal hypertension model was established by five-sixth nephrectomy operation (5/6Nx) in male Sprague Dawley rats. Ten weeks afterwards, they were random assigned to no treatment, or intracerebroventricular injection (ICV) with artificial cerebrospinal fluid, losartan [angiotensin II receptor type 1 (AT1R) antagonist], farnesylthiosalicylic acid (Ras inhibitor), PD98059 (MEK inhibitor), or SB203580 (p38 inhibitor) and Z-DEVD-FMK (caspase-3 inhibitor). Before and after treatment, physiological and biochemical indices were measured. Immunohistochemistry, western blot and RT-PCR were applied to quantify key components of renin-angiotensin system, apoptosis-related proteins, Ras-GTP, and MAPKs in the PVN samples. TUNEL assay was used to measure the situ apoptosis in PVN. Results: The 5/6Nx rats showed significantly elevated systolic blood pressure, urinary protein excretion, serum creatinine, and plasma norepinephrine (p < 0.05) compared to sham rats. The expression of angiotensinogen, Ang II, AT1R, p-ERK1/2, or apoptosis-promoting protein Bax were 1.08-, 2.10-, 0.74-, 0.82-, 0.83-fold higher in the PVN of 5/6Nx rats, than that of sham rats, as indicated by immunohistochemistry. Western blot confirmed the increased levels of AT1R, p-ERK1/2 and Bax; meanwhile, Ras-GTP and p-p38 were also found higher in the PVN of 5/6Nx rats, as well as the apoptosis marker cleaved caspase-3 and TUNEL staining. In 5/6Nx rats, ICV infusion of AT1R antagonist, Ras inhibitor, MEK inhibitor or caspase-3 inhibitor could lower systolic blood pressure (20.8-, 20.8-, 18.9-, 14.3%-fold) together with plasma norepinephrine (53.9-, 57.8-,63.3-, 52.3%-fold). Western blot revealed that blocking the signaling of AT1R, Ras, or MEK/ERK1/2 would significantly reduce PVN apoptosis as indicated by changes of apoptosis-related proteins (p < 0.05). AT1R inhibition would cause reduction in Ras-GTP and p-ERK1/2, but not vice versa; such intervention with corresponding inhibitors also suggested the unidirectional regulation of Ras to ERK1/2. Conclusion: These findings demonstrated that the activation of renin-angiotensin system in PVN could induce apoptosis through Ras/ERK1/2 pathway, which then led to increased sympathetic nerve activity and renal hypertension in 5/6Nx rats.

Project description:Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We sought to test the hypothesis that renovascular hypertension, induced by unilateral renal artery stenosis, exacerbates cardiac remodeling in leptin-deficient (db/db) mice, which serves as a model of human type II diabetes. Methods. We employed a murine model of renovascular hypertension through placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 wild-type (non-diabetic, WT) and 95 db/db mice subjected to renal artery stenosis (RAS) or sham surgery studied at 1, 2, 4, and 6+ weeks following surgery. Cardiac remodeling was assessed by quantitative analysis of the percent of myocardial surface area occupied by interstitial fibrosis tissue, as delineated by trichrome stained slides. Aortic pathology was assessed by histologic sampling of grossly apparent structural abnormalities or by section of ascending aorta of vessels without apparent abnormalities. Results. We noted an increased mortality in db/db mice subjected to RAS. The mortality rate of db/db RAS mice was about 23.5%, whereas the mortality rate of WT RAS mice was only 1.5%. Over 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection, predominantly in the ascending aorta and proximal descending aorta. Aortas from db/db RAS mice showed more smooth muscle dropout, loss of alpha smooth muscle actin expression, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db/db RAS model provides the basis for future studies directed towards defining basic mechanisms underlying the interaction of hypertension and diabetes on the development of aortic lesions.

Dataset Information

In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension.

Publications

In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets