title: Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro.
abstract: Renal tubulointerstitial fibrosis is the common and final pathologic change of kidney in end-stage renal disease. Interesting, endoplasmic reticulum (ER) stress is known to contribute to the pathophysiological mechanisms during the development of renal fibrosis. Here, we investigated the effects of chemical chaperon sodium 4-phenylbutyrate (4-PBA) on renal fibrosis in vivo and in vitro. In a rat unilateral ureteral obstruction (UUO) model, 4-PBA mimicked endogenous ER chaperon in the kidneys and significantly reduced glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), activating transcription factor 4 (ATF4), and phosphorylated JNK protein expressions as well as restored spliced X-box-binding protein 1 (XBP1) expressions in the kidneys of UUO rats. 4-PBA also attenuated the increases of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF) protein expressions, tubulointerstitial fibrosis, and apoptosis in the kidneys of UUO rats. Moreover, transforming growth factor (TGF)-β markedly increased ER stress-associated molecules, profibrotic factors, and apoptotic markers in the renal tubular cells (NRK-52E), all of which could be significantly counteracted by 4-PBA treatment. 4-PBA also diminished TGF-β-increased CTGF promoter activity and CTGF mRNA expression in NRK-52E cells. Taken together, our results indicated that 4-PBA acts as an ER chaperone to ameliorate ER stress-induced renal tubular cell apoptosis and renal fibrosis.
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-Chin
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan.|Superintendent's Office, National Taiwan University Hospital, Chu-Tung Branch, Taipei, Taiwan.
authors.forename: Ding-Cheng
authors.initials: DC
authors.lastname: Chan
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Tien
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Dentistry, Taipei Chang Gang Memorial Hospital, Chang Gang University, Taipei, Taiwan.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jenq-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuan-Yu
authors.initials: KY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005355:Fibrosis / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000473:pathology*; D008297:Male; D018832:Molecular Chaperones / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D018832:Molecular Chaperones; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid
keywords: apoptosis; endoplasmic reticulum stress; renal fibrosis; sodium 4-phenylbutyrate; unilateral ureteral obstruction