POS-402 UNCOUPLING PROTEIN 1 (UCP1) INHIBITS EPITHELIAL MESENCHYMAL TRANSFORMATION AND EXTRACELLULAR MATRIX AGGREGATION IN RENAL INTERSTITIAL FIBROSIS THROUGH SIRT3 DEPENDENT REACTIVE OXYGEN SPECIES (ROS) PATHWAY

Abstract

Renal interstitial fibrosis is a common pathological process of all chronic kidney diseases (CKD) developing to end-stage renal disease (ESRD). It is characterized by inflammatory cell infiltration, massive accumulation of extracellular matrix (ECM), disappearance of renal proper cells and reduction of microvessels. At present, although the research on renal interstitial fibrosis is gradually in-depth, its diagnosis and treatment methods are still very scarce. Therefore, to clarify the new pathogenesis of renal interstitial fibrosis and develop new methods for early diagnosis and treatment of renal interstitial fibrosis has become the focus and difficulty of current renal diseases research. Uncoupling protein-1 (UCP1) is the most important marker of brown adipose tissue (BAT), located in the inner membrane of the mitochondria. UCP1 can promote mitochondrial inner membrane proton conduction and decouple ATP synthesis from cellular respiration. The current research on UCP1 mainly focuses on fat metabolism, but its function in CKD has not been reported yet. Western blot, immunoblot analysis and immunohistochemistry were used to detect the expression of UCP1. UCP1 over expression lentivirus and UCP1 agonist CL316243 were used to upregulate UCP1. EMT related markers, collagen I, fibronectin, antioxidant enzyme SOD2 and CAT were detected by western blot and immunofluorescence. ROS detection kit was used to show the ROS production. SIRT3 knockdown was achieved by siRNA. This study firstly discovers that UCP1 is significant downregulated in patients with renal fibrosis and unilateral ureteral obstruction (UUO) animal model. Further research finds that upregulation of UCP1 can reverse the epithelial mesenchymal transformation (EMT) and ECM accumulation in renal fibrosis model both in vivo and in vitro. Meanwhile, UCP1 reduces the production of reactive oxygen species (ROS) by increasing the stability of SIRT3, which is weakened when SIRT3 is knocked down. Accordingly, this study proposes a scientific hypothesis in which UCP1 relieve EMT, ECM accumulation and renal interstitial fibrosis by increasing the stability of SIRT3 and decreasing the production of ROS. It will provide new ideas and targets for the treatment of CKD.