Wang Ru, Qu Jianchang, Chen Meiqiong, Han Tenglong, Liu Zhipeng, Wang Huizhong
Department of Laboratory Medcine, The 305 Hospital of PLA, No.13 Wenjin Street, Xicheng District, Beijing, 100017, China.
Department of Endocrinology, The 305 Hospital of PLA, No.13 Wenjin Street, Xicheng District, Beijing, 100017, China.
Int Urol Nephrol. 2025 Feb;57(2):643-653. doi: 10.1007/s11255-024-04214-2. Epub 2024 Oct 9.
N5-methylcytosine (m5C) methylation is involved in various disease progression; however, its role in diabetic nephropathy (DN) has not been studied. The aim of this study was to investigate the role of NSUN2 in DN and the underlying mechanism.
Streptozotocin-induced experimental mouse model was generated to analyze the role of NSUN2 in vivo, and high glucose (HG)-treated Raw264.7 cells were used to assess the effect of NSUN2 on macrophage infiltration in vitro. The regulation of NSUN2 on SOCS1 m5C methylation was evaluated using m5C methylated RNA immunoprecipitation, luciferase reporter analysis, and RNA stability determination assay.
The results indicated that NSUN2 was highly expressed in the blood and kidney of DN mice. Knockdown of NSUN2 alleviated kidney damage, reduced blood glucose and urine albumin, and suppressed macrophage infiltration in DN mice. Moreover, NSUN2 interacted with SOCS1, and silenced NSUN2 inhibited m5C levels of SOCS1 to reduce SOCS1 mRNA stability. Additionally, interference with NSUN2 suppressed macrophage migration, invasion, and infiltration by positively regulating SOCS1 expression under HG conditions.
In conclusion, silencing of NSUN2 inhibits macrophage infiltration by reducing m5C modification of SOCS1, and thereby attenuates renal injury. The findings suggest a novel regulatory mechanism between NSUN2-mediated m5C modification and DN.
N5-甲基胞嘧啶（m5C）甲基化参与多种疾病进展；然而，其在糖尿病肾病（DN）中的作用尚未得到研究。本研究旨在探讨NSUN2在DN中的作用及潜在机制。
构建链脲佐菌素诱导的实验性小鼠模型以分析NSUN2在体内的作用，并使用高糖（HG）处理的Raw264.7细胞评估NSUN2在体外对巨噬细胞浸润的影响。使用m5C甲基化RNA免疫沉淀、荧光素酶报告基因分析和RNA稳定性测定试验评估NSUN2对SOCS1 m5C甲基化的调控。
结果表明，NSUN2在DN小鼠的血液和肾脏中高表达。敲低NSUN2可减轻DN小鼠的肾脏损伤，降低血糖和尿白蛋白，并抑制巨噬细胞浸润。此外，NSUN2与SOCS1相互作用，沉默NSUN2可抑制SOCS1的m5C水平以降低SOCS1 mRNA稳定性。此外，在HG条件下，干扰NSUN2通过正向调节SOCS1表达抑制巨噬细胞迁移、侵袭和浸润。
总之，沉默NSUN2可通过降低SOCS1的m5C修饰抑制巨噬细胞浸润，从而减轻肾损伤。这些发现提示了NSUN2介导的m5C修饰与DN之间的一种新的调控机制。
