Agborbesong Ewud, Zhou Julie Xia, Zhang Hongbing, Li Linda Xiaoyan, Harris Peter C, Calvet James P, Li Xiaogang
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Biomedicines. 2024 Mar 7;12(3):603. doi: 10.3390/biomedicines12030603.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in mutant mouse and human ADPKD kidneys. Genetic knockout of in a knockout mouse model delayed cyst growth and improved kidney function compared with single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.
常染色体显性多囊肾病（ADPKD）是全球最常见的遗传性肾脏疾病，并会发展为终末期肾病（ESRD）。然而，其确切机制尚未完全明确。近年来，表观遗传重编程对囊肿生长的影响日益受到关注。然而，鉴于表观遗传机制的复杂性以及ADPKD中表观遗传成分的广泛改变，确定更具体的表观遗传因素并了解它们如何在促进囊肿生长方面存在机制联系，对于ADPKD治疗方法的开发具有重要意义。在此，我们发现通过组蛋白H3赖氨酸4三甲基化（H3K4me3）激活基因转录的组蛋白甲基转移酶SMYD3在突变小鼠和人类ADPKD肾脏中上调。与Smyd3单敲除小鼠肾脏相比，在Pkd1敲除小鼠模型中对Smyd3进行基因敲除可延缓囊肿生长并改善肾功能。免疫染色和蛋白质印迹分析表明，SMYD3在Pkd1突变的肾上皮细胞和组织中调节与增殖、凋亡和细胞周期效应器相关的PKD1信号通路。此外，我们发现SMYD3定位于中心体，并通过赖氨酸40处α-微管蛋白的甲基化调节有丝分裂和胞质分裂。此外，SMYD3调节Pkd1突变小鼠肾脏中的初级纤毛组装。总之，我们的结果表明SMYD3的过表达促进囊肿进展，并提示将SMYD3作为ADPKD的潜在治疗策略。
