Association of Retinoic Acid Receptors with Extracellular Matrix Accumulation in Rats with Renal Interstitial Fibrosis Disease

Yao-Bin Long,Tian-Biao Zhou,Yuan-Han Qin,Feng-Ying Lei

doi:10.3390/ijms131114073

Abstract

The nuclear retinoic acid receptors (RARs) function as ligand-dependent transcriptional regulators and include three subtypes (RARα, RARβ and RARγ), which control the expression of specific gene subsets subsequent to ligand binding and to strictly controlled phosphorylation processes. Extracellular matrix (ECM) accumulation is the most important characteristic of renal interstitial fibrosis (RIF). This study was performed to investigate whether RARs were associated with ECM accumulation in the progression of RIF in rats. Eighty Wistar male rats were divided into a sham operation group (SHO) and a model group subjected to unilateral ureteral obstruction (GU) at random; n = 40, respectively. The RIF disease in GU group was established by left ureteral ligation. The renal tissues were collected at two weeks and four weeks after surgery. Protein expressions of RARα, RARβ, RARγ, transforming growth factor-βl (TGF-β1), collagen-IV (Col-IV) and fibronectin (FN) were detected using immunohistochemical analysis, and mRNA expressions of RARα, RARβ, RARγ and TGF-β1 in renal tissue were detected by real time reverse transcription polymerase chain reaction. RIF index in renal interstitium was also calculated. When compared with those in SHO group, expressions of RARα and RARβ (protein and mRNA) were markedly reduced in the GU group (each p < 0.01). There was no marked difference for the expression of RARγ (protein and mRNA) between the SHO group and the GU group. The expressions of TGF-β1, Col-IV, FN and the RIF index in the GU group were markedly increased when compared with those in the SHO group (each p < 0.01). The protein expression of RARα/RARβ was negatively correlated with protein expression of TGF-β1, Col-IV or FN and the RIF index (all p < 0.01). In conclusion, the low expression of RARα/RARβ is associated with ECM accumulation in the progression of RIF in rats, suggesting that RARα/RARβ is a potentially therapeutic target for prevention of RIF.

Highlights

The retinoic acid receptors (RARs) function as ligand-dependent transcriptional regulators and include three subtypes (RARα, RARβ and RARγ), which control the expression of specific gene subsets subsequent to ligand binding and to strictly controlled phosphorylation processes [1,2]
The RARα or RARβ staining in the GU group (B3 and B4 for RARα, and C3 and C4 for RARβ; Figure 2) was markedly lower when compared with that in the sham operation group (SHO) group (B1 and B2 for RARα, and C1 and C2 for RARβ; Figure 2), especially in 4-week
Positive stainings for TGF-βl, Col-IV and FN were stronger in the area of Extracellular matrix (ECM) in the GU group compared to those in the SHO group, especially in week four of the GU group

Summary

Introduction

The retinoic acid receptors (RARs) function as ligand-dependent transcriptional regulators and include three subtypes (RARα, RARβ and RARγ), which control the expression of specific gene subsets subsequent to ligand binding and to strictly controlled phosphorylation processes [1,2]. There were lots of studies reporting that alterations of RARs expressions were associated with the development of some diseases, such as squamous-cell carcinoma [4], mammary carcinomas [5], esophageal cancer [6], etc. The role of RARs is complicated, and the mechanisms of RARs in the progression of diseases are not elucidated. RARs act as ligands for the metabolism of retinoic acid, and retinoic acid binds and activates the RARs and plays an essential role in many basic biological processes, such as cell proliferation, differentiation and apoptosis [8]

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Discussion

Conclusion