The data suggest that the hypertension and sympathoexcitation in 2K-1C rats were associated with an increase in oxidative stress within the RVLM, the PVN and systemically.
There is increasing evidence to support the hypothesis that reactive oxygen species (ROS) play a role in the pathophysiology of arterial hypertension. The ROS, particularly the superoxide anions (O 2 − ), are important intracellular messengers for Angiotensin II (Ang II) action in the brain. Ang II increases the activity of NAD(P)H oxidase, the major source of O 2 − in the vasculature, and enhances O 2 − production, both systemically and in the central nervous system. 1,2,3 For instance, intracerebroventricular infusion of NAD(P)H oxidase inhibitor antagonizes the increase in renal sympathetic nerve activity (RSNA) and the pressor response induced by centrally mediated Ang II actions. 3,4 In the brain, overexpression of superoxide dismutase (SOD), the enzyme responsible for O 2 − breakdown, also abolishes the central pressor effect of the octapeptide. 5 There is evidence to suggest that the central nervous system is involved in the development and maintenance of arterial hypertension. 6 However, the precise mechanisms by which the central nervous system participates in the evolution of arterial hypertension remains unclear and depends on the specific origin and phase of the hypertensive state. It is well known that in the 2K-1C (two-kidney one-clip) Goldblatt hypertension, the rostral ventrolateral medulla (RVLM) is one of the most important regions involved in the hypertension. 7 Therefore, the first aim of the present study was to examine whether there is an increase in oxidative stress within the RVLM in 2K-1C hypertension. For this purpose, the NAD(P)H oxidase subunits (p47phox and gp91phox) and CuZnSOD mRNA expression were quantified in the RVLM of 2K-1C hypertensive rats.Tai et al. 8 found that in SHR, elevated O 2 − radical production in the RVLM was associated with increased sympathetic nervous system activity; however, this mechanism had not been tested in a renovascular hypertension model. The second aim of the present study was therefore to examine whether oxidative stress is involved in the maintenance of sympathetic vasomotor tone and hypertension in 2K-1C rats. For this purpose, we injected directly into the RVLM the antioxidant ascorbic acid (vitamin C-Vit C), that acts as a free radical Background Oxidative stress is a state in which excess reactive oxygen species (rOS) overwhelm endogenous antioxidant systems. It is known that this state has been involved in the development of hypertension. On the basis of previous data, we hypothesized that overactivity of naD(P)H oxidase-derived rOS and the lowered activity of CuZnSOD, an endogenous antioxidant within the rostral ventrolateral medulla (rVLM), could contribute to 2K-1C (two-kidney one-clip) hypertension. Moreover, to test the functional significance of whether oxidative stress was involved in the maintenance of sympathetic vasomotor tone and blood pressure in 2K-1C hypertension, we administered ascorbic acid (Vit C), an antioxidant, into the rVLM or systemically.
Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×105 cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.
Despite extensive use of the renovascular/Goldblatt model of hypertension—2K-1C, and the use of renal denervation to treat drug resistant hypertensive patients, autonomic mechanisms that underpin the maintenance of this hypertension are important yet remain unclear. Our aim was to analyse cardiovascular autonomic function by power spectral density analysis of both arterial pressure and pulse interval measured continuously by radio telemetry for 6 weeks after renal artery clipping. Mean arterial pressure increased from 106 ± 5 to 185 ± 2 mm Hg during 5 weeks post clipping when it stabilized. A tachycardia developed during the 4th week, which plateaued between weeks 5 and 6. The gain of the cardiac vagal baroreflex decreased immediately after clipping and continued to do so until the 5th week when it plateaued (from − 2.4 ± 0.09 to − 0.8 ± 0.04 bpm/mm Hg; P < 0.05). A similar time course of changes in the high frequency power spectral density of the pulse interval was observed (decrease from 13.4 ± 0.6 to 8.3 ± 0.01 ms2; P < 0.05). There was an increase in both the very low frequency and low frequency components of systolic blood pressure that occurred 3 and 4 weeks after clipping, respectively. Thus, we show for the first time the temporal profile of autonomic mechanisms underpinning the initiation, development and maintenance of renovascular hypertension including: an immediate depression of cardiac baroreflex gain followed by a delayed cardiac sympathetic predominance; elevated sympathetic vasomotor drive occurring after the initiation of the hypertension but coinciding during its mid-development and maintenance.
Abstract-Reactive oxygen species in peripheral cardiovascular tissues are implicated in the pathogenesis of 2 kidney-1 clip hypertension. We recently identified an imbalance between reactive oxygen species generation and oxidant scavenging in the rostral ventrolateral medulla (RVLM) of 2 kidney-1 clip in rats. We tested whether enhanced superoxide signaling in RVLM of 2 kidney-1 clip rats contributes to the chronic hypertension via sympathetic activation in conscious rats. We enhanced superoxide scavenging in RVLM by overexpressing cytoplasmically targeted superoxide dismutase using an adenoviral vector (Ad-CMV-CuZnSOD) in Wistar rats (male, 150 to 180 g) in which the left renal artery was occluded partially 3 weeks earlier. Hypertension was documented using radiotelemetry recording of arterial pressure in conscious rats for 6 weeks. Renovascular hypertension elevated both serine phosphorylation of p47phox subunit of NADPH and superoxide levels in RVLM. The elevated superoxide levels were normalized by expression of CuZnSOD in RVLM. Moreover, the hypertension produced in the 2 kidney-1 clip rats was reversed 1 week after viral-mediated expression of CuZnSOD. This antihypertensive effect was maintained and associated with a decrease in the low-frequency spectra of systolic blood pressure variability, suggesting reduced sympathetic vasomotor tone. The expression of CuZnSOD was localized to RVLM neurons, of which some contained tyrosine hydroxylase. None of the above variables changed in control rats receiving Ad-CMV-eGFP in RVLM. In Goldblatt hypertension, superoxide signaling in the RVLM plays a major role in the generation of sympathetic vasomotor tone and the chronic sustained hypertension in this animal model. (Hypertension. 2010;56:290-296.)Key Words: hypertension Ⅲ renal Ⅲ blood pressure Ⅲ heart rate Ⅲ brain Ⅲ free radicals I nvolvement of oxidative stress in the pathology of arterial hypertension was reported in various animal models, including the renovascular 2 kidney-1 clip (2K-1C), 1-3 the 1 kidney-1 clip, 4 angiotensin II (Ang II)-induced hypertension, [5][6][7] Dahl salt-sensitive (desoxycorticosterone acetate-salt) hypertension, 8 spontaneously hypertensive rats (SHRs), 9,10 and strokeprone SHRs. 11,12 In addition, oxidative stress also plays an important role in humans with renovascular hypertension 13 and essential hypertension. 14 From these studies it is clear that oxidative stress acts at the level of the vascular wall but also within the brain. The renin-angiotensin-aldosterone system plays a major role in the 2K-1C model. 15 Ang II stimulates superoxide (O 2 ⅐Ϫ ) radical generation by increasing the activity of NADPH oxidase within peripheral blood vessel walls. 16 -18 However, there is evidence that reactive oxygen species (ROS) in the brain are involved in neuronal signaling, contributing to sympathoexcitation and hypertension. 12,19 Intracerebroventricular infusion of an NADPH oxidase inhibitor antagonizes both the increase in renal sympathetic nerve activity and pressor response ind...
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