School of pharmacy, Fudan University, Shanghai 201203, China.
Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Genes (Basel). 2022 Nov 29;13(12):2244. doi: 10.3390/genes13122244.
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease and continues to be a threat to patients with diabetes. Dysfunction of glomerular mesangial cells (GMCs) is the main contributing factor to glomerulosclerosis, which is a pathological feature of DN. The epigenetic factor ASH2L has long been thought to be a transcriptional activator, but its function and involvement in diabetic nephropathy is still unclear. Here, we investigated the effect of ASH2L on the regulation of fibrosis and inflammation induced by high glucose in mouse mesangial cells (mMCs). We observed that ASH2L expression is increased in high glucose-induced mMCs, while loss of ASH2L alleviated fibrosis and inflammation. Furthermore, ASH2L-mediates H3K4me3 of the homeodomain-interacting protein kinase 2 (HIPK2) promoter region, which is a contributor to fibrosis in the kidneys and promotes its transcriptional expression. Similar to loss of ASH2L, silencing HIPK2 also inhibited fibrosis and inflammation. In addition, ASH2L and HIPK2 are upregulated in the kidneys of both streptozocin-induced and db/db mouse. In conclusion, we uncovered the crucial role of ASH2L in high glucose-induced fibrosis and inflammation, suggesting that ASH2L regulation may be an attractive approach to attenuate the progression of DN.
糖尿病肾病 (DN) 是终末期肾病的主要原因，并且仍然对糖尿病患者构成威胁。肾小球系膜细胞 (GMC) 的功能障碍是肾小球硬化的主要促成因素，肾小球硬化是 DN 的病理特征。表观遗传因子 ASH2L 长期以来被认为是一种转录激活因子，但它在糖尿病肾病中的功能和作用仍不清楚。在这里，我们研究了 ASH2L 对高糖诱导的小鼠系膜细胞 (mMC) 中纤维化和炎症的调节作用。我们观察到，ASH2L 在高糖诱导的 mMC 中表达增加，而 ASH2L 的缺失减轻了纤维化和炎症。此外，ASH2L 介导同源结构域相互作用蛋白激酶 2 (HIPK2) 启动子区域的 H3K4me3，这是肾脏纤维化的一个贡献者，并促进其转录表达。与 ASH2L 的缺失类似，沉默 HIPK2 也抑制了纤维化和炎症。此外，ASH2L 和 HIPK2 在链脲佐菌素诱导和 db/db 小鼠的肾脏中均上调。总之，我们揭示了 ASH2L 在高糖诱导的纤维化和炎症中的关键作用，表明 ASH2L 的调节可能是减轻 DN 进展的一种有吸引力的方法。
