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Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

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Abstract

Angiotensin II (Ang II), a major effector of the renin–angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor-κB (NF-κB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-κB activation are not fully understood. The purpose of this study was to document altered molecular events involved in age-related changes in Ang II signaling and NF-κB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-κB by phosphorylating IκBα and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IκB kinase αβ, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-κB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia.

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Acknowledgments

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST, No.2009-0083538).

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Authors and Affiliations

  1. Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735, South Korea

    Ji Min Kim, Hyoung-Sam Heo, Young Mi Ha, Byeong Hyeok Ye, Eun Kyeong Lee, Yeon Ja Choi & Hae Young Chung

  2. College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735, South Korea

    Ji Min Kim, Hyoung-Sam Heo, Young Mi Ha, Byeong Hyeok Ye, Eun Kyeong Lee, Yeon Ja Choi & Hae Young Chung

  3. Department of Physiology, University of Texas Health Science Center, San Antonio, TX, 78229-3900, USA

    Byung Pal Yu

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  1. Ji Min Kim
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Kim, J.M., Heo, HS., Ha, Y.M. et al. Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging. AGE 34, 11–25 (2012). https://doi.org/10.1007/s11357-011-9207-7

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