Du Xinyu, Shen Fengchen, Yu Chao, Wang Yanjin, Yu Jianjun, Yao Liyuan, Liu Na, Zhuang Shougang
Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.
FASEB J. 2025 May 15;39(9):e70533. doi: 10.1096/fj.202500089R.
The protein SET and MYND-Domain Containing 3 (SMYD3) is a methyltransferase that modifies various non-histone and histone proteins, linking it to tumorigenesis and cyst formation. However, its role in acute kidney injury (AKI) remains unclear. This study investigates the role and mechanism of AKI using a murine model of ischemia-reperfusion (IR)-induced AKI. After IR injury, SMYD3 and H3K4me3 levels increased in the kidneys, correlating with renal dysfunction, tubular cell injury, and apoptosis. Administration of BCI-121, a selective SMYD3 inhibitor, exacerbated IR-induced tubular cell injury and apoptosis, leading to more severe renal dysfunction and pathological changes. Pharmacological inhibition of SMYD3 also impaired the dedifferentiation and proliferation of renal tubular cells, key regenerative processes in injured kidneys, as evidenced by decreased expression of vimentin, snail, proliferating cell nuclear antigen (PCNA), cyclin D1, and retinoblastoma protein (RB). Additionally, SMYD3 inhibition reduced phosphorylation of the epithelial growth factor receptor (EGFR) and AKT, as well as EGFR expression in damaged kidneys. Finally, both BCI-121 and SMYD3 siRNA reduced EGF-induced expression of vimentin, snail, cyclin D1, PCNA, and EGFR, along with phosphorylation of RB and AKT in cultured renal tubular cells. Chip assay indicated that SMYD3 and H3K4me3 are enriched at the promoter of EGFR and SMYD3 inhibition blocked this response. These data suggest that SMYD3 plays an important role as an epigenetic regulator of renal tubular cell survival and regenerative pathways following kidney injury. Targeting SMYD3 or its epigenetic effects could offer therapeutic potential for enhancing kidney regeneration in AKI and related renal diseases.
含SET和MYND结构域蛋白3（SMYD3）是一种甲基转移酶，可修饰多种非组蛋白和组蛋白，与肿瘤发生和囊肿形成有关。然而，其在急性肾损伤（AKI）中的作用仍不清楚。本研究使用缺血再灌注（IR）诱导的AKI小鼠模型，研究了SMYD3在AKI中的作用及机制。IR损伤后，肾脏中SMYD3和H3K4me3水平升高，与肾功能障碍、肾小管细胞损伤和凋亡相关。给予选择性SMYD3抑制剂BCI-121会加剧IR诱导的肾小管细胞损伤和凋亡，导致更严重的肾功能障碍和病理变化。对SMYD3的药理学抑制也损害了肾小管细胞的去分化和增殖，这是受损肾脏中的关键再生过程，波形蛋白、蜗牛蛋白、增殖细胞核抗原（PCNA）、细胞周期蛋白D1和视网膜母细胞瘤蛋白（RB）表达降低证明了这一点。此外，抑制SMYD3可降低受损肾脏中表皮生长因子受体（EGFR）和AKT的磷酸化以及EGFR的表达。最后，BCI-121和SMYD3 siRNA均可降低培养的肾小管细胞中EGF诱导的波形蛋白、蜗牛蛋白、细胞周期蛋白D1、PCNA和EGFR的表达，以及RB和AKT的磷酸化。芯片分析表明，SMYD3和H3K4me3在EGFR启动子处富集，抑制SMYD3可阻断这一反应。这些数据表明，SMYD3作为肾损伤后肾小管细胞存活和再生途径的表观遗传调节因子发挥重要作用。靶向SMYD3或其表观遗传效应可能为增强AKI及相关肾脏疾病的肾脏再生提供治疗潜力。
