Retinoic acid receptors α and γ are involved in antioxidative protection in renal tubular epithelial cells injury induced by hypoxia/reoxygenation

Abstract

Renal interstitial fibrosis (RIF) is a common outcome in various chronic kidney diseases. Injury to renal tubular epithelial cell (RTEC) is major link in RIF. Hypoxia is one of the common factors for RTEC damage. Retinoic acid receptors (RARs), RARα, RARβ and RARγ, are evolutionary conserved and pleiotropic proteins that have been involved in various cellular functions, including proliferation, differentiation, apoptosis, and transcription. Recently, we discovered that aberrant expression of RARs was involved in the development of RIF in rats. Here, we investigated the role of RARs in the hypoxia/reoxygenation (HR) damage model in RTEC with virus-based delivery vectors to knockdown or overexpress RARs. Relevant indicators were detected. Our results showed that HR inhibited RARα and RARγ expressions in a time-dependent manner in RTECs; however, the expression of RARβ was not changed obviously. RARα and RARγ overexpression could protect cells from oxidative stress-induced injury by inhibiting HR-induced intracellular superoxide anion (O₂⁻) generation, cell viability and mitochondria membrane potential (MMP) decrease and transforming growth factor β1 (TGF-β1) expression and promoting endogenous antioxidant defense components, superoxide dismutase (SOD) and glutathione (GSH). Meanwhile, inhibition of RARα and RARγ expressions by small interference RNAs (siRNA) resulted in a less resistance of RTEC to HR as shown in increased O₂⁻ production and TGF-β1 expression and decreased cell viability, MMP, SOD and GSH levels. These data indicates that RARα and RARγ act as positive regulators to offset oxidative damage and profibrosis cytokine accumulation and therefore has an antioxidative effect.

Keywords:

• Hypoxia/reoxygenation
• oxidative stress
• renal interstitial fibrosis
• renal tubular epithelial cells
• retinoic acid receptors

Disclosure statement

All authors declare that there are no conflicts of interest in this work.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant no. 81560119, the Projects for Development of Appropriate Technology of Health Care in Guangxi under Grant no. S201522 and Innovation Project of Graduate Student Education in Guangxi under Grant no. YCSZ2015107.