METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy.

BACKGROUND: Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone methyltransferase that has been demonstrated to regulate insulin secretion and glucose concentration. This study focused on the role of NSD2 in the renal impairment during diabetic nephropathy (DN).

METHODS: Serum NSD2 level in patients with DN was examined, and its correlations with the renal impairment-related indicators were examined. A murine model of DN was established, and mouse mesangial cells (SV40-MES-13) were treated with high-glucose (HG) to mimic a DN-like condition in vitro. Overexpression of NSD2 was introduced into mice or cells for in vivo and in vitro studies. The m6A level in HG-treated SV40-MES-13 cells was analyzed. METTL3 expression and its correlation with NSD2 were determined.

RESULTS: NSD2 was poorly expressed in the serum of patients with DN and was negatively correlated with the levels of fasting blood sugar (FBG), serum creatinine (SCr), serum cystatin C (S-Cys-C), the 24-h urine protein (24-h U-protein) and the urine cystatin C (U-Cys-C). NSD2 overexpression reduced the kidney weight and reduced renal impairment in mice. It also suppressed interstitial fibrosis in mouse kidney tissues and reduced fibrosis-related markers in HG-treated SV40-MES-13 cells. HG treatment reduced the m6A level in the cells. METTL3 promoted m6A modification of NDS2 mRNA and enhanced its stability by YTHDF1. METTL3 overexpression alleviated renal impairment and fibrosis in vivo and in vitro. But the protective role was blocked upon NSD2 silencing.

CONCLUSION: This study demonstrates that METTL3 promotes NSD2 mRNA stability by YTHDF1 to alleviate progression of DN.