Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Activation of proinflammatory signaling by 4-hydroxynonenal-Src adducts in aged kidneys

Eun Ji Jang, Dae Hyun Kim, Bonggi Lee, Eun Kyeong Lee, Ki Wung Chung, Kyoung Mi Moon, Min Jo Kim, Hye Jin An, Ji Won Jeong, Ye Ra Kim, Byung Pal Yu and Hae Young Chung _

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Oncotarget. 2016; 7:50864-50874. https://doi.org/10.18632/oncotarget.10854

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Abstract

Eun Ji Jang1,*, Dae Hyun Kim1,*, Bonggi Lee1, Eun Kyeong Lee1, Ki Wung Chung1, Kyoung Mi Moon1, Min Jo Kim1, Hye Jin An1, Ji Won Jeong1, Ye Ra Kim1, Byung Pal Yu2 and Hae Young Chung1

1 Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea

2 Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America

* These authors have contributed equally to this work

Correspondence to:

Hae Young Chung, email:

Keywords: 4-HNE; Src; aged kidney; inflammation; cell senescence; Gerotarget

Received: November 06, 2015 Accepted: July 17, 2016 Published: July 26, 2016

Abstract

In our previous study, reactive 4-hydroxy-2-nonenal (4-HNE) was shown to activate Src (a non-receptor tyrosine kinase) by forming an adduct on binding with a specific residue of Src, leading to the activation of proinflammatory signaling pathways in cultured cells. However, to date, the deleterious roles of 4-HNE in inflammatory signaling activation in kidneys during aging have not been explored. The purpose of the present study was to document the mechanisms by which 4-HNE induces inflammation in the kidney during aging. Initial experiments revealed that activated nuclear factor-κB (NF-κB) expression was caused by 4-HNE activation, which suppressed transcriptional activity in the aged kidney. Treatment of human umbilical vein endothelial cells with 4-HNE revealed that Src caused senescence via NF-κB activation. Furthermore, our immunohistochemistry data showed that 4-HNE-adducted Src significantly increased in aged kidney tissues. The data showed age-related upregulation of downstream signaling molecules such as mitogen activated protein kinases (MAPKs), activator protein-1 (AP-1), NF-κB, and COX-2 in a cell culture cell system.

Taken together, the results of this study show that the formation of adducts between 4-HNE and Src activates inflammatory signaling pathways in the aged kidney, contributing to age-related nephropathy.


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