Oncotarget

Research Papers:

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

Shing-Hwa Liu _, Ching-Chin Yang, Ding-Cheng Chan, Cheng-Tien Wu, Li-Ping Chen, Jenq-Wen Huang, Kuan-Yu Hung and Chih-Kang Chiang

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Oncotarget. 2016; 7:22116-22127. https://doi.org/10.18632/oncotarget.7904

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Abstract

Shing-Hwa Liu1,2,3,*, Ching-Chin Yang1,*, Ding-Cheng Chan4,5,6,*, Cheng-Tien Wu1, Li-Ping Chen7, Jenq-Wen Huang4, Kuan-Yu Hung4, Chih-Kang Chiang1,4,8

1Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

2Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

3Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

4Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

5Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan

6Superintendent’s Office, National Taiwan University Hospital, Chu-Tung Branch, Taipei, Taiwan

7Department of Dentistry, Taipei Chang Gang Memorial Hospital, Chang Gang University, Taipei, Taiwan

8Department 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: [email protected]

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.


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