Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Transl Res. 2024 Feb;264:85-96. doi: 10.1016/j.trsl.2023.10.002. Epub 2023 Oct 23.
Diabetic nephropathy (DN) is one of the complications of diabetes. Long-term hyperglycemia in the kidney results in renal insufficiency, and eventually leads to end-stage renal disease. Epigenetic factor ASH2L has long been identified as a transcriptional activator, and we previously indicated that ASH2L aggravated fibrosis and inflammation in high glucose-induced glomerular mesangial cells, but the pathophysiological relevance and the mechanism of ASH2L-mediated H3K4me3 in DN is not well understood. Here we demonstrated that ASH2L is upregulated in glomeruli isolated from db/db mice. Loss of ASH2L protected glomerular injury caused by hyperglycemia, as evidenced by reduced albuminuria, preserved structure, decreased glomerular extracellular matrix deposition, and lowered renal glomerular expression of proinflammatory and profibrotic markers in db/db mice. Furthermore, we demonstrated that enrichment of ASH2L-mediated H3K4me3 on the promoter regions of ADAM17 and HIPK2 triggered their transcription, leading to aberrant activation of Notch1 signaling pathway, thereby contributing to fibrosis and inflammation in DN. The findings of this study provide compelling evidence for targeting ASH2L as a potential therapeutic strategy to prevent or slow down the progression of DN.
糖尿病肾病 (DN) 是糖尿病的并发症之一。肾脏长期的高血糖会导致肾功能不全，最终导致终末期肾病。表观遗传因子 ASH2L 长期以来一直被认为是一种转录激活因子，我们之前的研究表明，ASH2L 加重了高糖诱导的肾小球系膜细胞中的纤维化和炎症，但 ASH2L 介导的 H3K4me3 在 DN 中的病理生理相关性和机制尚不清楚。在这里，我们证明了 ASH2L 在从 db/db 小鼠分离的肾小球中上调。ASH2L 的缺失保护了高血糖引起的肾小球损伤，表现为白蛋白尿减少、结构保存、肾小球细胞外基质沉积减少以及 db/db 小鼠肾脏肾小球中促炎和促纤维化标志物的表达降低。此外，我们证明了 ASH2L 介导的 H3K4me3 在 ADAM17 和 HIPK2 启动子区域的富集触发了它们的转录，导致 Notch1 信号通路的异常激活，从而导致 DN 中的纤维化和炎症。这项研究的结果为靶向 ASH2L 作为一种潜在的治疗策略提供了有力的证据，以预防或减缓 DN 的进展。
