Involvement of the transcription factors NF-kB and Nrf2 in aldosterone induced DNA damage

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Nicole Schupp

University of Düsseldorf, Germany

: Forensic Toxicol Pharmacol 2015, 4:3

Abstract

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Epidemiological studies found an increased risk for kidney cancer in hypertensive patients. These patients frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. We investigated, in vitro and in vivo ; the capacity of kidney cells to upregulate transcription factors like NF-κB and Nrf2. Aldosterone activated the pro-survival factor NF-κB in vitro and in vivo and led to the expression of anti-apoptotic proteins like Bcl-2. The NF-κB-inhibitor PDTC reduced DNA damage in kidney cells. Further, aldosterone activated the regulator of the antioxidative defense, Nrf2 in vitro and in vivo and increased the expression of enzymes involved in glutathione synthesis and detoxification. The activation of the two transcription factors was mediated by the mineralocorticoid receptor (MR) and oxidative stress. In vitro, while at 24 h of aldosterone exposure oxidant levels remained high, a decrease in Nrf2 activation, glutathione, and target gene levels was observed. Nrf2 activation therefore could not protect cells against oxidative DNA damage, since aldosterone-induced double strand breaks and 8-oxodG lesions steadily rose. Administration of the Nrf2 activator sulforaphane enhanced the Nrf2 response in vitro and in vivo and thereby prevented aldosterone-induced DNA damage. Aldosterone-induced DNA damage triggers the activation of NF-κB and Nrf2. Inhibition of NF- κB, as well as activation of Nrf2 decrease DNA damage. Schupp@uni-duesseldorf.de

Biography

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Schupp@uni-duesseldorf.de