Abstract
Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. Therefore, the effective therapies against renal fibrosis are urgently needed. The objective of this study was to investigate the effect of Am80, a synthetic retinoic acid receptor (RAR) agonist, in the treatment of renal interstitial fibrosis using unilateral ureteral obstruction (UUO) mice. The findings indicate that Am80 treatment suppressed renal fibrosis and inflammation to the same degree as the naturally-occuring retinoic acid, all-trans retinoic acid (atRA). But the adverse effect of body weight loss in Am80-treated mice was lower compared to the atRA treatment. The hepatic mRNA levels of alpha-1-acid glycoprotein (AGP), a downstream molecule of RAR agonist, was increased following administration of Am80 to healthy mice. In addition, increased AGP mRNA expression was also observed in HepG2 cells and THP-1-derived macrophages that had been treated with Am80. AGP-knockout mice exacerbated renal fibrosis, inflammation and macrophage infiltration in UUO mice, indicating endogenous AGP played an anti-fibrotic and anti-inflammatory role during the development of renal fibrosis. We also found that no anti-fibrotic effect of Am80 was observed in UUO-treated AGP-knockout mice whereas atRA treatment tended to show a partial anti-fibrotic effect. These collective findings suggest that Am80 protects against renal fibrosis via being involved in AGP function.
Highlights
Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury
The results for qRTPCR showed that the mRNA expression of α-SMA and Col1a2 were increased in ureteral obstruction (UUO) mice that had received the corn oil treatment, and these mRNA levels were significantly suppressed to the same degree in mice that had been treated with either Am80 or all-trans retinoic acid (atRA) (Fig. 1b)
The qRT-PCR results showed that the expression of IL-6 and IL-1β mRNA were both increased in the UUO mice, and these expressions were significantly suppressed by treatment with either Am80 or atRA (Fig. 1d)
Summary
Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. (UUO)-induced renal fibrosis model[8], and retinoids have protective effects in numerous types of renal damage and inflammation including acute pyelonephritis[9] and glomerulosclerosis in adriamycin-induced nephropathy model[10,11] In addition, Chiba et al reported that atRA treatment reduced macrophage-dependent injury and fibrosis after an acute kidney injury (AKI), where atRA functioned to regulate macrophage a ctivation[12]. These collective studies indicate that retinoids play a protective role in renal injury. The detailed mechanism of how retinoids protect against renal fibrosis is not fully understood
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