Hyperglycemia-induced overexpression of CREB3 L3 promotes the epithelial-to-mesenchymal transition in bladder urothelial cells in diabetes mellitus.

Diabetic cystopathy (DCP) is a complication affecting the lives of people with diabetes. However, the pathogenesis of DCP is not well known. To investigate the potential mechanisms by which cAMP-responsive element-binding protein 3 like 3 (CREB3 L3) promotes the occurrence and development of DCP. High-throughput sequencing was used to analyze differentially expressed genes (DEGs) in bladder urothelium from patients with DCP and healthy controls. Gene enrichment analysis was conducted to assess the biological functions of DEG. Small interfering RNA technology was performed to silence the CREB3 L3 gene in both in vitro and in vivo experiments. Morphological changes in bladder urothelium from a DCP rat model were observed. Immunofluorescence and western blotting assay were performed to determine associated protein expression. We identified significant DEGs through high-throughput sequencing. These genes were primarily enriched in inflammatory activation, epithelial-mesenchymal transition (EMT) and tight junction organization. Upregulated expression of both CREB3 L3 and C-reactive protein (CRP) in bladder urothelium from patients with DCP was accompanied by upregulated EMT markers including N-cadherin and vimentin proteins, but downregulated E-cadherin. Silencing CREB3 L3 attenuated the protein expression of CRP and EMT in SV-HUC-1 urothelial cells under hyperglycemic conditions and in the diabetes mellitus rat model at 4, 8, and 12 weeks. CREB3 L3 knockdown also reversed downregulation of the tight junction proteins occludin and claudin 1. Hyperglycemia induces the upregulation of CREB3 L3 expression, thereby promoting the EMT and impairing tight junctions in bladder urothelial cells. Targeting CREB3 L3 in bladder urothelial cells is likely to be a key approach in preventing and treating DCP.