Department of Clinical Laboratory, Liyang People's Hospital, No. 70, Jianshe West Road, Licheng Town, Liyang, 213300, Jiangsu, P. R. China.
BMC Nephrol. 2022 Mar 30;23(1):124. doi: 10.1186/s12882-022-02753-3.
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).
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.
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.
This study demonstrates that METTL3 promotes NSD2 mRNA stability by YTHDF1 to alleviate progression of DN.
核受体结合 SET 域蛋白 2（NSD2）是一种组蛋白甲基转移酶，已被证明可调节胰岛素分泌和葡萄糖浓度。本研究关注 NSD2 在糖尿病肾病（DN）期间肾损伤中的作用。
检测了 DN 患者血清 NSD2 水平，并检测了其与肾损伤相关指标的相关性。建立了 DN 小鼠模型，并在体外使用高糖（HG）处理小鼠系膜细胞（SV40-MES-13）以模拟 DN 样条件。将 NSD2 过表达引入小鼠或细胞进行体内和体外研究。分析了 HG 处理的 SV40-MES-13 细胞中的 m6A 水平。确定了 METTL3 的表达及其与 NSD2 的相关性。
DN 患者血清中 NSD2 表达水平较低，与空腹血糖（FBG）、血清肌酐（SCr）、血清胱抑素 C（S-Cys-C）、24 小时尿蛋白（24-h U-protein）和尿胱抑素 C（U-Cys-C）水平呈负相关。NSD2 过表达降低了小鼠的肾脏重量并减轻了肾损伤。它还抑制了小鼠肾组织中的间质纤维化，并降低了 HG 处理的 SV40-MES-13 细胞中的纤维化相关标志物。HG 处理降低了细胞中的 m6A 水平。METTL3 通过 YTHDF1 促进 NSD2 mRNA 的 m6A 修饰并增强其稳定性。METTL3 过表达在体内和体外减轻了肾损伤和纤维化。但是，沉默 NSD2 后阻断了这种保护作用。
本研究表明，METTL3 通过 YTHDF1 促进 NSD2 mRNA 稳定性，从而缓解 DN 的进展。
