title: Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development.
abstract: Several animal studies have shown an important role for endoplasmic reticulum (ER) stress in AKI, whereas human studies are lacking. We recently reported that Reticulon-1A (RTN1A) is a key mediator of ER stress and kidney cell injury. Here, we investigated whether modulation of RTN1A expression during AKI contributes to the progression to CKD. In a retrospective study of 51 patients with AKI, increased expression of RTN1A and other ER stress markers were associated with the severity of kidney injury and with progression to CKD. In an inducible tubular cell-specific RTN1A-knockdown mouse model subjected to folic acid nephropathy (FAN) or aristolochic acid nephropathy, reduction of RTN1A expression during the initial stage of AKI attenuated ER stress and kidney cell injury in early stages and renal fibrosis development in later stages. Treatment of wild-type mice with tauroursodeoxycholic acid, an inhibitor of ER stress, after the induction of kidney injury with FA facilitated renoprotection similar to that observed in RTN1A-knockdown mice. Conversely, in transgenic mice with inducible tubular cell-specific overexpression of RTN1A subjected to FAN, induction of RTN1A overexpression aggravated ER stress and renal injury at the early stage and renal fibrosis at the late stage of FAN. Together, our human and mouse data suggest that the RTN1A-mediated ER stress response may be an important determinant in the severity of AKI and maladaptive repair that may promote progression to CKD.
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.|Department of Medicine, Division of Nephrology, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.|Department of Medicine, Division of Nephrology, and.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Medicine, Division of Nephrology, and.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Fadi
authors.initials: F
authors.lastname: Salem
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fei
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Hongda
authors.initials: H
authors.lastname: Bao
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Xinhua Hospital, Shanghai, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Xinhua Hospital, Shanghai, China.
authors.forename: Gengru
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Nephrology, Second Military Medical University Affiliated Changhai Hospital, Shanghai, China; and.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; cijiang.he@mssm.edu wangniansong2012@163.com.
authors.forename: Niansong
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Nephrology, and cijiang.he@mssm.edu wangniansong2012@163.com.|Renal Section, James J Peters VA Medical Center, Bronx, New York.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D051436:Renal Insufficiency, Chronic / Q000209:etiology; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D009419:Nerve Tissue Proteins; C081781:RTN1 protein, human
keywords: ER stress; acute kidney injury; renal fibrosis; renal tubular epithelial cells; reticulon-1