The impetus sparking this scientific inquiry is the result of many studies that have shown protective effects of plant-based diets on cardiovascular disease (CVD) and cancer. Many bioactive compounds, such as polyphenols which typically occur in small quantities in foods, can in vitro activate the cellular antioxidant system, and several animal studies have demonstrated their favorable effects on CVD including hypertension. However, plant products per se or traditional antioxidants like vitamins failed to have a positive impact on renal or cardiovascular health during clinical studies. This is despite the considerable evidence from both hypertensive animal models and patients showing that hypertension is closely associated with oxidative stress. Studies from our lab and others show that renal specific oxidative stress could be an independent risk factor for systemic hypertension. It is well established that kidney natriuretic factors especially dopamine via D1 receptor (D1R) activation play a pivotal role in maintaining sodium homeostasis and regulating blood pressure. We have shown that renal D1R are down-regulated by oxidative stress leading to decrease in sodium excretion and hypertension. Therefore, endogenous molecules which could reduce oxidative stress and protect renal D1R signaling will be highly beneficial in maintaining sodium balance and systemic pressure. We found that Ang 1-7, a beneficial member of the renin-angiotensin system could activate the redox- sensitive transcription factor Nrf2 which is involved in the transcriptional activation of antioxidant genes to protect the cells against oxidative stress. We hypothesized that Ang 1-7 via Nrf2 activation could protect renal D1R function and reduce blood pressure. Our preliminary studies show that pharmacologically-induced oxidative stress transcriptionally down-regulated renal D1R which attenuated D1R dependent inhibition of renal sodium transporters and increased blood pressure in wild type and renal proximal tubule-specific Nrf2 knockout mice. However, the oxidative stress, onset and severity of hypertension and renal D1R dysfunction were more robust in Nrf2 knockout compared to wild type mice. More importantly, Ang 1-7 activated Nrf2, reduced oxidative stress, normalized renal D1R function and eliminated hypertension in wild type mice but failed to protect D1R function or reduce BP in Nrf2 knockout mice. Further studies showed that oxidative stress-induced hypertension is also more severe in renal proximal tubule-specific PPAR? (peroxisome proliferator- activated receptor gamma, a pleiotropic nuclear receptor expressed in kidney tissue) knockout mice and Ang 1-7 fails to protect renal PPAR? knockout mice from hypertension. Additional experiments in human proximal tubular (HK2) cells also indicated that Ang 1-7 via Nrf2?PPAR? activation protected renal D1R function. These findings led us to hypothesize that Ang 1-7 via Nrf2 activation reduces oxidative stress, normalizes renal D1R signaling and prevents hypertension during oxidative stress. Mechanistically, Ang 1-7-mediated Nrf2 induction activates PPAR? which protects renal D1R function and mitigates hypertension.
An imbalance in natriuretic and antinatriuretic factors due to increased oxidative stress can disrupt sodium regulation in kidneys which can lead to hypertension. Although the role of oxidative stress as a risk factor in the development of hypertension seems to be settled, the favorable effects of exogenous antioxidants on cardiovascular health are highly controversial. Therefore, shifting focus on endogenous molecules which could trigger cellular antioxidant defense system could be a paradigm shift in countering cardiovascular diseases. Our studies provide novel mechanistic insights into antihypertensive benefits of such a molecule i.e. Ang 1-7. We found a precise pathway which identifies how Ang 1-7 intervention protects renal proximal tubular D1R function and mitigates hypertension.