Abstract 72: Redox-sensitive Transcriptional Regulation of Renal Dopamine D1 Receptor Function during Hypertension

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Oxidative stress plays an important role in the development of hypertension. We and others have shown that renal dopamine D1 receptor (D1R), a major contributor to sodium homeostasis and BP regulation, is negatively regulated by oxidative stress. It is reported that antioxidants can reduce BP and redox-sensitive transcription factor Nrf2 could provide important clues for antihypertensive properties of antioxidants. Here in we investigated the signaling molecules responsible for redox-sensitive renal proximal tubular D1R dysfunction and how the induction of renal specific Nrf2, in response to antioxidants, will protect D1R function and reduce BP. Wild type (WT) and renal proximal tubular specific Nrf2 knockout (KO) mice were treated with 10 mM L-buthionine-sulfoximine (BSO, a pro-oxidant) without and with sulforaphane (S, a polyphenol antioxidant; 5 μM daily by gavage) for 5 wks. In WT mice, BSO treatment increased oxidative stress and BP (mm Hg, WT: 104 ± 3, WT-BSO: 125 ± 5), reduced renal tubular D1R expression and attenuated SKF38393 (a D1R agonist)-induced Na/K-ATPase inhibition and sodium excretion. BSO also activated transcription factors activator protein (AP) 1 and SP3. However, the onset and severity of hypertension (BP, Nrf2-KO: 101 ± 3, Nrf2-KO-BSO: 137 ± 4) as well as oxidative stress, activation of AP1 and SP3 and D1R dysfunction were more robust in BSO-treated Nrf2 KO compared to WT mice. More importantly, sulforaphane activated Nrf2, reduced oxidative stress, normalized AP1 and SP3 activation, rescued DIR function and lowered BP (WT-S: 97 ± 4, WT-BSO+S: 109 ± 6) in BSO-treated WT mice but failed to normalize renal D1R function or reduce BP (Nrf2-KO-S: 99 ± 3, Nrf2-KO-BSO+S: 131 ± 4) in Nrf2 KO mice. Further experiments in human proximal tubular cultures revealed that BSO via AP1 activated SP3 which in turn transcriptionally down-regulated D1R expression and sulforaphane, via Nrf2 activation, abolished BSO-induced AP1 and SP3 activation and protected D1R function. In conclusion, oxidative stress via AP1-SP3 pathway down-regulates D1R expression and function which leads to sodium retention and hypertension. Antioxidants, via Nrf2 activation, reduce oxidative stress and normalize AP1-SP3 signaling and D1R function which reduces BP.

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