WITHDRAWN: RIP140 mediates hyperglycemia-induced glucotoxicity in β-cells via the activation of JNK and ERK1/2 signaling pathways.

Abstract AIMS: To investigate the role of RIP140 in pancreatic β-cells under glucotoxic conditions. METHODS: Murine insulinoma cell line MIN6 cells were transfected with RIP140 overexpression plasmid or RIP140 siRNA before exposure to 25mM glucose, then cells viability and cells in early apoptosis, intracellular free fatty acid and insulin secretion were measured. mRNA abundance of peroxisome proliferation-activated receptor γ coactivator 1α (PGC-1α), phosphoenulpyruvate carboxykinase (PEPCK), pancreatic and duodenal homebox 1 (PDX-1), uncoupling protein 2 (UCP-2) and proliferating cell nuclear antigen (PCNA) were detected. The phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and B cell lymphoma/leukemia-2 (Bcl-2) protein levels were evaluated by Western blotting. RESULTS: Upregulating RIP140 declined cells viability, increased early apoptotic cells and decreased insulin secretion of hyperglycemia-treated MIN6 cells, whereas downregulating RIP140 protected β-cells against hyperglycemia-induced apoptosis and elevated insulin secretion under hyperglycemia conditions. RIP140 overproduction depressed PGC-1α, PEPCK, PDX-1, PCNA mRNA levels and elevated UCP-2 mRNA levels in 25mM glucose-treated MIN6 cells, whereas RIP140 inhibition had the contrary results. Furthermore, RIP140 increased phosphorylated JNK and ERK1/2 levels and reduced Bcl-2 level in the presence of 25mM glucose. CONCLUSIONS: Our results suggest that RIP140 mediates β-cell apoptosis, insulin secretion decline and specific genes transcription under glucotoxic conditions via the activation of JNK and ERK1/2 signaling pathways.