title: Activation of proinflammatory signaling by 4-hydroxynonenal-Src adducts in aged kidneys.
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.
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Jang
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Bonggi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Kyoung Mi
authors.initials: KM
authors.lastname: Moon
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Min Jo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: An
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Ye Ra
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D019061:src-Family Kinases; C027576:4-hydroxy-2-nonenal
keywords: 4-HNE; Gerotarget; Src; aged kidney; cell senescence; inflammation