Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro

// Shing-Hwa Liu 1, 2, 3, * , Ching-Chin Yang 1, * , Ding-Cheng Chan 4, 5, 6, * , Cheng-Tien Wu 1 , Li-Ping Chen 7 , Jenq-Wen Huang 4 , Kuan-Yu Hung 4 , Chih-Kang Chiang 1, 4, 8 1 Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan 3 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 4 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan 6 Superintendent’s Office, National Taiwan University Hospital, Chu-Tung Branch, Taipei, Taiwan 7 Department of Dentistry, Taipei Chang Gang Memorial Hospital, Chang Gang University, Taipei, Taiwan 8 Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Chih-Kang Chiang, e-mail: ckchiang@ntu.edu.tw Keywords: sodium 4-phenylbutyrate, endoplasmic reticulum stress, unilateral ureteral obstruction, apoptosis, renal fibrosis Received: January 11, 2016      Accepted: February 21, 2016      Published: March 03, 2016 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.