Abstract 364: Nrf2-PPAR gamma Signaling Suppresses Exaggerated Renal Tubular AT1R Gene Expression and Function and Mitigates Hypertension During Oxidative Stress

Abstract

Oxidative stress plays an important role in the development of hypertension. Interestingly, angiotensin type 1 receptor (AT1R) function, a major contributor to the etiology of hypertension, is positively regulated by oxidative stress. It is shown that antioxidant treatment can reduce blood pressure (BP) and redox-sensitive transcription factor Nrf2 could provide important clues for antihypertensive properties of antioxidants. Here in we investigated how induction of renal proximal tubular Nrf2 in response to antioxidants will activate PPAR gamma (a pleiotropic nuclear receptor whose ligands exhibit BP reducing effects) which in turn will normalize AT1R expression 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, an antioxidant; 5 μM daily by gavage) for 5 wks. BSO-treatment increased oxidative stress, AT1R mRNA, AT1R expression and Ang II-induced activation of renal sodium transporters and these animals exhibited high BP (mm Hg, WT: 102±3, WT-BSO: 123±4, Nrf2 KO: 98±2). However, the onset and severity of hypertension (Nrf2-KO-BSO: 136±4) as well as oxidative stress and AT1R function was more robust in BSO-treated Nrf2 KO compared to WT mice. More importantly, sulforaphane activated Nrf2, reduced oxidative stress, normalized proximal tubular AT1R function and reduced BP (WT-S: 99±5, WT-BSO+S: 106±6) in BSO-treated WT mice but failed to mitigate AT1R function or reduce BP (Nrf2 KO-S: 97±4, Nrf2 KO-BSO+S: 130±3) in Nrf2 KO mice. Further studies showed that BSO-induced hypertension is also more severe in renal proximal tubular specific PPAR gamma KO mice and sulforaphane fails to protect PPAR gamma KO mice from hypertension. Experiments in human renal proximal tubular cells indicated that 1) sulforaphane, via Nrf2 activation, reduced oxidant-induced AT1R upregulation and 2) Nrf2 dependent PPAR gamma activation suppresses AT1R gene transcription. These findings suggest that antioxidants via Nrf2 activation reduce oxidative stress, normalize AT1R signaling and prevent hypertension during oxidative stress. More importantly, Nrf2 induction activates PPAR gamma which suppresses AT1R gene transcription.