Response to “Does Angiotensin-Dependent Superoxide Production Help to Prevent Salt-Induced Endothelial Dysfunction in 2 Kidney–1 Clip Hypertensive Rats?”

To the Editor: We recently reported the surprising finding that the salt-induced endothelial dysfunction and downregulation of copper (Cu)/zinc (Zn) superoxide dismutase (SOD) that occurred in cerebral arteries of sham-operated animals were absent in 2 kidney–1 clip (2K1C) hypertensive rats, which exhibit prolonged elevations of plasma angiotensin II (ANG II) levels, and that AT1 receptor blockade with losartan eliminated endothelium-dependent vasodilation in 2K1C rats.1 We concluded that the elevated ANG II levels in the 2K1C rats played a key role in protecting against salt-induced vascular dysfunction and suppression of Cu/Zn SOD by upregulating antioxidant defense mechanisms in the arteries. In a letter to the editor entitled “Could AT1 Receptor Activation Increase Antioxidant Defense to Prevent Salt-Induced Vascular Dysfunction of 2 Kidney-1 Clip Hypertensive Rats?”, Dr Valdir A. Braga stated that it is difficult to draw conclusions about the vascular actions of ANG II without looking at oxidant enzymes and downstream production of reactive oxygen species. Braga cites a list of well-known and indisputable findings showing that ANG II, acting via AT1 receptors, activates NADPH oxidase to produce superoxide (O2 −) radicals and that ANG II has been linked to oxidative stress in the context of vascular dysfunction and hypertension. Based on those conclusions, Braga suggests that the upregulation of Cu/Zn SOD occurs in response to increases in O2 − rather than a possible antioxidant effect of ANG II. In our estimation, Braga’s conclusion that O2 − production in response to the elevated ANG II levels in the 2K1C rats may play an important role in preventing salt-induced endothelial dysfunction through upregulation of Cu/Zn SOD is quite plausible and could provide an explanation for the surprising findings in our study (i.e., the “antioxidant effect” of ANG II to upregulate Cu/Zn SOD in 2K1C rats). In support of that hypothesis, Papaiahgari et al.2 reported that O2 − produced by NADPH oxidase was essential to activate the ERK 1/2 pathway in C10 alveolar epithelial cells exposed to hyperoxia and that this led to upregulation of the nuclear transcription factor Nrf2, which upregulates multiple antioxidant and cell protective enzymes, including Cu/Zn SOD. Consistent with those findings, McEwen et al.3 showed that the protective effect of low-dose ANG II infusion to restore vascular relaxation mechanisms in cerebral arteries of salt-fed Sprague-Dawley rats is eliminated by AT1 receptor blockade and by inhibiting the ERK 1/2 pathway. Further emphasizing the importance of physiological levels of ANG II in maintaining normal vascular function is our recent study,4 which showed that diet-induced obesity, which is known to elevate plasma ANG II levels, restores normal endothelial function in a model of chronically low levels of plasma ANG II, the Dahl salt-sensitive rat.The precise mechanisms by which O2 − radicals formed by NADPH oxidase in response to elevated ANG II levels contribute to maintenance of antioxidant defense mechanisms (including Cu/Zn SOD) in 2K1C hypertensive rats remain to be determined. However, investigation of the relationship between ANG II levels, vascular O2 −, and activation of the Nrf2 antioxidant defense system appears to be a promising avenue of investigation.