Mechanism of attenuation of pro-inflammatory Ang II-induced NF-κB activation by genistein in the kidneys of male rats during aging

Abstract

Angiotensin II (Ang II), a main effector of the renin-angiotensin system, is recognized as a pro-inflammatory mediator on age-related vascular inflammation. Ang II is one of the most important oxidative stress inducer, activates the redox-sensitive transcription factor, nuclear factor-κB (NF-κB) during aging. Genistein, a major component found in isoflavone, has anti-inflammatory activities that are often associated with its anti-oxidative activity. The purpose of this study is to document molecular mechanism of altered Ang II-related NF-κB activation during aging and inhibitory molecular events by genistein regarding to age-related Ang II-induced NF-κB activation. At present, we utilized young (6 months old), old (24 months old), and genistein-treated (2 and 4 mg/kg/day for 10 days) old rats. For our current study, we choose to use the kidney and rat endothelial cell line, YPEN-1 because of its vulnerability to age-related oxidative stress and inflammatory responsiveness. The results of the analysis showed that Ang II and AT1 expression increased during aging and that these increases were blunted by treatment with genistein. Furthermore, we investigated the inhibitory effects of genistein on the Ang II-induced redox imbalance in aged rat kidneys. Genistein reduced age-related increases in NF-κB activity and NF-κB-dependent pro-inflammatory genes expression. We also determined genistein attenuated Ang II-induced NF-κB activation through its anti-oxidant activity in YPEN-1 cells. Taken together, our present results show that genistein has potent anti-inflammatory effect resulting in the attenuation of the Ang II-induced NF-κB activation during aging. The most significant new finding from this study is that genistein exerts its anti-Ang II action during aging by suppressive effect of NF-κB activation. Based on these data, genistein may be an anti-Ang II agent that may be used in anti-inflammatory therapies.

Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress

“…The AT1R is the main target receptor of Ang II and it plays a key role in blood pressure regulation, vasoconstriction and oxidative stress [10–12], whereas the AT2R typically plays an opposing, protective role in such responses [13–15]. We confirmed that renal AT1R expression is increased in old age [3, 16] – a known effect of the actions of IL-1β and TNF-α [17] – both of which were also upregulated here. Moreover, there was a profound reduction in vascular AT2R expression during aging such that the ratio of AT1R/AT2R expression was markedly increased in mesenteric arteries, providing a plausible mechanism for the markedly augmented pressor and contractile responses to infusion of low-dose Ang II.…”

Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study

“…We found that injection of Aβ 1–40 into the rat brain was associated with astrocytic hypertrophy and this event was significantly inhibited by genistein. Previous studies have demonstrated that genistein has an anti-inflammatory impact on conditions such as diabetes [18] and on various types of tissue, including retina [19], gut [20], respiratory organs [21], kidney [22], and arthritic joints [23,24]. Genistein exerts its anti-inflammatory effect by influencing transcription factors, enzymes, and inflammatory mediators that are involved in inducing inflammation.…”

Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s disease type: possible involvement of PPAR-γ agonistic property

“…The RAS in the CNS may contribute to the disease process of CNS disorders including AD, probably through neuronal death and memory dysfunctions. 9,56,57 High levels of angiotensin II are reported to contribute to oxidative stress 58 and inflammation 59 which produce deleterious effects in the CNS. It has been noted that ACEIs may provide benefits in cognition beyond blood pressure control.…”