Abstract

Aberrant DNA methylation patterns have been linked to diverse pathological conditions, including chronic kidney diseases. However, it remains unclear whether DNA methyltransferase 1 (DNMT1) affects renal tubular function in diabetic nephropathy (DN) DNMT1 and neurofibromatosis type 2 (NF2) expression levels were assessed using quantitative real-time PCR, Western blotting, immunohistochemical, and immunofluorescence analyses. The methylation status of the NF2 promoter was assessed through methylation-specific PCR and bisulfite genomic sequencing PCR. Cell viability was evaluated using the MTT assay, and cell apoptosis was quantified through flow cytometry analysis. Additionally, inflammatory responses were evaluated by quantifying IL-1β and IL-6 concentrations with enzyme-linked immunosorbent assays. DNMT1 expression was markedly elevated in the renal samples of DN patients and db/db mice. The DNA methylation inhibitor 5-aza-2′-deoxycytidine alleviated kidney tubular injury in db/db mice, and it also reduced inflammatory responses and cell apoptosis in HK-2 cells exposed to high glucose (HG). Hypermethylation of the NF2 promoter was observed in HK-2 cells exposed to HG. Furthermore, DNMT1 knockdown was found to protect against cell apoptosis and inflammatory injury by modulating NF2 expression. These results demonstrated that DNMT1 can inhibit renal tubular cell apoptosis and inflammation in DN by regulating NF2 expression, which may have therapeutic applications in the development and treatment of DN. Graphical DNMT1 suppression alleviated apoptosis and inflammatory responses in DN by modulating NF2 methylation. DNMT1 expression is markedly upregulated in hyperglycemia condition, resulting in hypermethylation of the NF2 promoter and subsequent activation of YAP. DNMT1/NF2/YAP signaling axis is a promising target for developing novel treatments for DN.