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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

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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

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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.

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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.

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