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

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), RAR alpha, RAR beta and RAR gamma, 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 RAR alpha and RAR gamma expressions in a time-dependent manner in RTECs; however, the expression of RAR beta was not changed obviously. RAR alpha and RAR gamma overexpression could protect cells from oxidative stress-induced injury by inhibiting HR-induced intracellular superoxide anion (O-2(-)) generation, cell viability and mitochondria membrane potential (MMP) decrease and transforming growth factor beta 1 (TGF-beta 1) expression and promoting endogenous antioxidant defense components, superoxide dismutase (SOD) and glutathione (GSH). Meanwhile, inhibition of RAR alpha and RAR gamma expressions by small interference RNAs (siRNA) resulted in a less resistance of RTEC to HR as shown in increased O-2(-) production and TGF-beta 1 expression and decreased cell viability, MMP, SOD and GSH levels. These data indicates that RAR alpha and RAR gamma act as positive regulators to offset oxidative damage and profibrosis cytokine accumulation and therefore has an antioxidative effect.