title: Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved.
abstract: Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. "Stimulated by retinoic acid 6" (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFβ1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1(-/-) mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Liang-Yin
authors.initials: LY
authors.lastname: Ke
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Divisions of Endocrinology and Metabolism Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Kun-Der
authors.initials: KD
authors.lastname: Lin
authors.affiliation: Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Chu
authors.affiliation: Divisions of Endocrinology and Metabolism Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Mei-Yueh
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Divisions of Endocrinology and Metabolism Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Departments of Internal Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Pi-Jung
authors.initials: PJ
authors.lastname: Hsiao
authors.affiliation: Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chin
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Vascular and Medical Research, Texas Heart Institute, Houston, TX cchen@texasheart.org sjshin@kmu.edu.tw.
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Divisions of Endocrinology and Metabolism Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Departments of Internal Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan cchen@texasheart.org sjshin@kmu.edu.tw.
authors.forename: Shyi-Jang
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D050171:Dyslipidemias / Q000150:complications / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; C108001:Stra6 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: lectin-like oxidized LDL receptor-1; renal tubular cells; stimulated by retinoic acid 6