Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells BothIn VitroandIn Vivo

Abstract

Aims: An increased kidney cancer risk was found in hypertensive patients, who frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. The capacity of kidney cells to up-regulate transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2), a key regulator of the cellular antioxidative defense, as a prevention of aldosterone-induced oxidative damage was investigated both in vitro and in vivo. Results: Aldosterone activated Nrf2 and increased the expression of enzymes involved in glutathione (GSH) synthesis and detoxification. This activation depended on the mineralocorticoid receptor (MR) and oxidative stress. In vitro, Nrf2 activation, GSH amounts, and target gene levels decreased after 24 h, while oxidant levels remained high. Nrf2 activation could not protect cells against oxidative DNA damage, as aldosterone-induced double-strand breaks and 7,8-dihydro-8-oxo-guanine (8-oxodG) lesions steadily rose. The Nrf2 activator sulforaphane enhanced the Nrf2 response both in vitro and in vivo, thereby preventing aldosterone-induced DNA damage. In vivo, Nrf2 activation further had beneficial effects on the aldosterone-caused blood pressure increase and loss of kidney function. Innovation: This is the first study showing the activation of Nrf2 by aldosterone. Moreover, the results identify sulforaphane as a substance that is capable of preventing aldosteroneinduced damage both in vivo and in vitro. Conclusion: Aldosterone-induced Nrf2 adaptive response cannot neutralize oxidative actions of chronically increased aldosterone, which, therefore could be causally involved in the increased cancer incidence of hypertensive individuals. Enhancing the cellular antioxidative defense with sulforaphane might exhibit beneficial effects. Antioxid. Redox Signal. 21, 2126-2142.

Oxidative DNA Damage in Kidneys and Heart of Hypertensive Mice Is Prevented by Blocking Angiotensin II and Aldosterone Receptors

“…While Nrf2 activation was not studied yet in AngII-induced hypertension, data from other hypertension models are conflicting. In mineralocorticoid-dependent hypertension Nrf2 mRNA and protein, as well as the target protein heme oxygenase-1 were upregulated, as seen in our mice [30] , [31] . In the spontaneously hypertensive rat, the Nrf2 response was impaired [32] , just as in models of kidney disease [33] , [34] .…”

Glutathionylation: a regulatory role of glutathione in physiological processes

“…Nrf2 signalling is also regulated by other posttranslational, transcriptional, translational, and epigenetic mechanisms, other signal proteins (e.g. p62, p21, and IQ motif-containing GTPase-activating protein) (45), and even hormones such as aldosterone (52). Another important regulator of the Nrf2/Keap1 complex is the thioreductase system, more specifically the selenoprotein thioredoxin reductase 1 (TRXR1, EC 1.8.1.9), a highly reactive enzyme.…”

Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor

“…The Nrf2 transcription factor (or NFE2L2) regulates genes involved in antioxidant defenses, including hemooxygenase 1 (HO1), SOD3, glutathione peroxidase (GPX), thioredoxin and peroxiredoxin (Ma 2013). In the kidney, aldosterone has been shown to activate Nrf2 in the context of hypertension-induced oxidative DNA damage (Queisser et al 2014). Contradicting results from animal studies show beneficial effects either of Nrf2 agonists administration in WT mice under highfat conditions or of Nrf2 knockout on metabolism and glucose homeostasis (Shin et al 2009, Pi et al 2010, Zhang et al 2012, Choi et al 2014, Schneider et al 2016.…”