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

// Eun Ji Jang 1,* , Dae Hyun Kim 1,* , Bonggi Lee 1 , Eun Kyeong Lee 1 , Ki Wung Chung 1 , Kyoung Mi Moon 1 , Min Jo Kim 1 , Hye Jin An 1 , Ji Won Jeong 1 , Ye Ra Kim 1 , Byung Pal Yu 2 and Hae Young Chung 1 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.