Research Papers: Gerotarget (Focus on Aging):
Activation of proinflammatory signaling by 4-hydroxynonenal-Src adducts in aged kidneys
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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
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
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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