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.