title: Albumin overload down-regulates integrin-β1 through reactive oxygen species-endoplasmic reticulum stress pathway in podocytes.
abstract: Proteinuria is a major hallmark of glomerular nephropathy and endoplasmic reticulum (ER) stress plays an important role in glomerular nephropathy. The protein levels of integrin-β1 in podocytes are found to be negative correlation with amount of proteinuria. This study investigated whether urinary protein, particularly albumin, induced ER stress that consequently reduced integrin-β1 expression. All experiments were performed using primary cultured rat podocyte. Protein and mRNA expression were measured by western blotting and semiquantified reverse transcriptase polymerase chain reaction. Albumin uptake was found at 1 h after albumin addition. Albumin reduced precursor and mature forms of integrin-β1, but did not change mRNA levels of integrin-β1. Albumin induced reactive oxygen species (ROS) generation and ER stress. Antioxidant (N-acetylcysteine) suppressed albumin-induced ER stress and decrements in precursor and mature forms of integrin-β1. Then, ER stress inhibitors (4-phenylbutyrate and salubrinal) also inhibited albumin-induced decrements in precursor and mature forms of integrin-β1. The potent ER stress inducers (thapsigargin and tunicamycin) directly decreased precursor and mature forms of integrin-β1 and led appearance of unglycosylated core protein of integrin-β1. Our results show that in proteinuric disease, albumin decreases precursor and mature forms of integrin-β1 through ROS-ER stress pathway in podocytes.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chun 1st Rd., Kaohsiung 80708, Taiwan;
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Division of Nephrology, Tainan Sinlau Hospital, No. 57, 1 Sec., Dongman Rd., Tainan, Taiwan; chen.chouml@msa.hinet.net.
authors.forename: Chien-An
authors.initials: CA
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, No. 482, Shanming Rd., Hsiaogang Dist., Kaohsiung 70812, Taiwan; and.
authors.forename: Jer-Ming
authors.initials: JM
authors.lastname: Chang
authors.affiliation: Division of Nephrology, Kaohsiung Medical University Hospital, No. 100, Shih-Chuan 1st Rd., Kaohsiung 80708, Taiwan chenhc@kmu.edu.tw.
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Chen
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008954:Models, Biological; D008970:Molecular Weight; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000418:Albumins; D019012:Integrin beta1; D017382:Reactive Oxygen Species; D014415:Tunicamycin; D019284:Thapsigargin
keywords: endoplasmic reticulum stress; glomerular nephropathy; integrin; podocyte; proteinuria