Redox sensitive transcription factors are pivotal in maintaining the normal oxidative milieu of cells. While an imbalance in redox status is implicated in hypertension, the link between this phenomenon and hypertension is not clear. In addition, it has been shown that many bioactive compounds, extranutritional constituents (nutraceuticals) that typically occur in small quantities in foods, have antioxidant properties and lower blood pressure, the exact mechanism for these beneficial effects is unclear. We, and others, have reported that renal dopamine via activation of D1 receptor (D1R) plays a major role in regulation of sodium homeostasis and blood pressure (BP). Renal D1R function is down-regulated in chronic diseases, especially in oxidative stress related hypertension and diabetes. Therefore, the identification of cellular molecules which contributes to D1R dysfunction as well as the mechanism by which dietary compounds can preserve renal D1R function will provide a novel therapeutic approach to mitigate hypertension. Transcription factors such as AP1 and SP3 play an important role in oxidative stress related pathophysiological conditions. Conversely, redox sensitive transcription factor Nrf2 activates a highly regulated defense system against oxidative stress which involves transcriptional activation of phase II defense and antioxidant genes. Our preliminary studies showed that mice treated with L-buthionine-sulfoximine (BSO), a glutathione synthesis pathway inhibitor exhibited oxidative stress, high BP, renal proximal tubular D1R dysfunction and up-regulation of AP1 and SP3. These phenomena were exaggerated in BSO-treated renal proximal tubule specific Nrf2 knockout mice. More importantly, sulforaphane (a polyphenol antioxidant) activated Nrf2, reduced oxidative stress, normalized AP1 and SP3 activation, preserved DIR function and lowered BP in BSO-treated wild type mice but failed to normalize renal D1R function or reduce BP in Nrf2 knockout mice. Further experiments in human kidney cells (a proximal tubular epithelial cell line) also indicated that: 1) BSO via AP1 activated SP3 which in turn transcriptionally down-regulated D1R expression and 2) sulforaphane, via Nrf2 activation, abolished BSO-induced AP1 and SP3 activation and D1R dysfunction. These findings led us to hypothesize that: 1) oxidative stress via AP1-SP3 pathway down-regulates D1R expression and function which leads to decrease in sodium excretion and hypertension and 2) antioxidants via Nrf2 activation reduce oxidative stress and normalize AP1-SP3 signaling and D1R function which reduces BP. Therefore, it is likely that polyphenols, such as sulforaphane and resveratrol, via activation of Nrf2 signaling would provide a novel mechanism to protect D1R function and mitigate hypertension during oxidative stress. These studies will have significant impact on understanding the mechanisms for potential public health benefits of antioxidants as recent studies in humans have shown that polyphenols and direct Nrf2 activators can reduce BP and improve kidney function in CKD and type 2 diabetic patients.

Public Health Relevance

Studies have suggested that oxidative stress is a major risk factor while polyphenols have favorable effects on cardiovascular diseases. However, the cause and effect relationship between oxidative stress and hypertension and mechanisms of beneficial effects of polyphenols is still elusive. Therefore, much scientific research needs to be conducted before we can begin to make evidence-based dietary recommendations of these compounds. Role of redox sensitive transcription factors in development or mitigation of hypertension could provide a novel therapeutic strategy to counter this multifactorial disease. Herein, we identified the precise pathway involving transcription factors AP1, SP3 and Nrf2 for development and mitigation of hypertension during oxidative stress. From a practical perspective, this translates into alternative therapeutic approach for hypertension by targeting specific activation of Nrf2 by antioxidants or diets rich in polyphenols.

National Institute of Health (NIH)
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Hypertension and Microcirculation Study Section (HM)
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Ketchum, Christian J
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University of Houston
Schools of Pharmacy
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Bhatt, Siddhartha R; Lokhandwala, Mustafa F; Banday, Anees Ahmad (2014) Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B. Clin Exp Hypertens 36:367-73
Banday, Anees Ahmad; Lokhandwala, Mustafa F (2013) Novel gastro-renal axis and sodium regulation during hypertension. Hypertension 62:834-5