Is antioxidant therapy effective for advanced hypertension and renal injury?

Inappropriate augmentation of reactive oxygen species (ROS) production reduces the bioavailability of antioxidant defenses [1,2] and plays a pivotal role in the pathophysiology of hypertension and renal injury [3–5]. Experimental studies have indicated that enhanced ROS production is involved in vascular remodeling and endothelium dysfunction during the development of hypertension [6]. Earlier clinical studies have also suggested a strong association between lower antioxidant levels and cardiovascular risks [7]. To date, much effort has been directed toward the benefits of antioxidant therapy. Clinical studies, including the Cambridge Heart Antioxidant Study [8] and the Antioxidant Supplementation in Atherosclerosis Prevention Study [9], have shown the beneficial effects of antioxidant therapy for cardiovascular events. Large epidemiological studies have also reported that dietary intake of antioxidants inversely correlates with hypertension [9,10]. Similarly, treatment with ascorbic acid significantly improved SBP and DBP in mild-to-moderate hypertensive patients [11]. In experimental models of hypertension, vitamin C alone or in combination with vitamin E increased the synthesis of nitric oxide and reduced blood pressure [12,13]. Furthermore, an antioxidant rich diet was shown to relieve hypertension and reduces renal immune cell infiltration [14]. By contrast, many clinical trials failed to demonstrate any beneficial effects of antioxidant therapy on blood pressure [15–17] and cardiovascular events [18–20]. For example, the Heart Protection Study Collaborative Group studied high-risk individuals and showed that although antioxidant vitamin supplementation substantially increased blood vitamin concentrations, it did not produce any significant reductions in the incidence of any type of cardiovascular disease [19]. In this issue of Journal of Hypertension, the article ‘Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats’ by Sugama et al.[21] shows that antioxidant therapy with a superoxide mimetic, tempol, did not reduce blood pressure in salt-loaded old stroke prone spontaneously hypertensive rats (SHRSP). The authors also showed that although tempol effectively reduced oxidative stress in the kidney, it actually exacerbated the progression of proteinuria and histological damage, such as glomerulosclerosis and interstitial fibrosis. These data suggest that alternative pathways that are ROS-independent are involved in the pathogenesis of the advanced stage of hypertension and renal injury in SHRSP. It is also possible that oxidative stress is merely a consequence of the activation of these alternative pathways. However, Park et al.[22] had performed similar experiments in SHRSP and shown that long-term treatment with tempol from early stages of hypertension did attenuate the progression of hypertension through the prevention of vascular remodeling, and that this was associated with decreased vascular superoxide production and increased plasma antioxidant levels. Thus, the question arises as to why antioxidant therapies show such conflicting results in clinical and experimental studies [23]. Importantly, it is clear from the clinical studies that dose differences do not seem to be responsible for such discrepant results [23]. One possible explanation for the discrepancy in these studies is the different stage of hypertension and renal injury. In both clinical and experimental studies, beneficial effects of antioxidants were mostly found when interventions were started at an early stage. For example, Park et al.[22] administered tempol from an early age and showed an attenuation in the development of hypertension in SHRSP, whereas Sugama et al.[21] failed to observe a blood pressure-lowering effect of tempol if treatment started at an advanced hypertensive stage. Inatomi et al.[24] have also shown that in patients with mild cardioembolic stroke, treatment with an antioxidant, edaravone, resulted in early functional improvement, but these effects were not observed in late stages. The finding that antioxidant therapies have no beneficial effects on advanced hypertension, as well as cardiovascular and renal diseases, suggest a potential involvement of systems other than ROS. Consistent with this idea, in their current article Sugama et al.[21] showed that treatment with an angiotensin II receptor blocker (ARB), candesartan, effectively decreased blood pressure and attenuated renal injury in advanced-stage SHRSP. Furthermore, although both tempol and candesartan reduced ROS in the kidney, only tempol did not improve hypertension and renal injury. These data suggest that in advanced-stage SHRSP, the renin–angiotensin system plays an important role in the pathogenesis of hypertension and renal injury through ROS-independent mechanisms. By contrast, previous studies in SHRSP showed that long-term treatment with an ARB from an early stage attenuates the progression of hypertension and renal injury, which are accompanied by reductions in ROS production [25]. Taken together, these data suggest that the pharmacological mechanisms responsible for the beneficial effects of ARBs may be different between early and advanced stages in SHRSP. In conclusion, current experimental evidence indicates that early antioxidant treatment can have beneficial effects on the development of hypertension as well as cardiovascular and renal diseases. However, antioxidants become much less effective during advance stages of these diseases. Future studies are needed to better understand the roles of these different pathways in the pathogenesis of these diseases, and which treatments are most effective at each stage. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.