Kidney-Induced Hypertension Depends on Superoxide Signaling in the Rostral Ventrolateral Medulla

Abstract

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...

Brain Angiotensin-II-derived Reactive Oxygen Species: Implications for High Blood Pressure

“…To date, we have shown that chronic peripheral Ang II infusion in mice produces a slow developing hypertension, which is accompanied of superoxide accumulation in the RVLM and increased sympathetic activity [30]. Similar results have been found in 2K1C rats [31]. Interestingly, scavenging of superoxide by adenovirus-mediated overexpression of Copper/Zinc Superoxide Dismutase (CuZnSOD) in the RVLM prevents both the accumulation of superoxide and the increase in sympathetic activity.…”

“…Regarding reactive oxygen species in the RVLM, our laboratory and others have shown that Ang II-derived superoxide anions accumulation in the RVLM is critical for the pathogenesis of neurogenic hypertension (Figure 1) [12,17,18,[30][31][32]. The increase of superoxide anions leads to changes in ion channels, particularly calcium and potassium channels, altering neuronal properties in RVLM resulting in increase in sympathetic nerve activity and increase in blood pressure [33].…”

Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

“…These findings support other reports showing brain ROS overproduction in the phenol renal injury model of hypertension 27 and the 2-kidney, 1-clip hypertension model. 28 ICV administration can act in the hypothalamic area, which is supposed to contain several nuclei critically involved in the cardiovascular regulation system, such as the subfornical organ, paraventricular hypothalamic nuclei, and organum vasculosum of the stria terminalis. Other regions of the brain, such as the RVLM, 28,41 have also been recognized as key areas that can mediate oxidative stress-induced sympathoexcitation.…”

“…28 ICV administration can act in the hypothalamic area, which is supposed to contain several nuclei critically involved in the cardiovascular regulation system, such as the subfornical organ, paraventricular hypothalamic nuclei, and organum vasculosum of the stria terminalis. Other regions of the brain, such as the RVLM, 28,41 have also been recognized as key areas that can mediate oxidative stress-induced sympathoexcitation. In contrast, previous studies that used ICV infusion of antioxidants, including those in our laboratory, suggest that the hypothalamus is a critical area for ROS generation and the maintenance of sympathetic control of the cardiovascular system.…”

“…Recently, central sympathetic activation has been reported to be mediated by brain ROS in the phenol renal injury model of hypertension 27 and in the 2-kidney, 1-clip hypertension model. 28 Thus, brain ROS overproduction might be a characteristic of hypertension associated with renal dysfunction. Therefore, we hypothesized that central sympathetic activation, possibly because of the overproduction of oxidative stress in the brain, could contribute to arterial pressure elevation in salt-induced CKD.…”