Zuo Siyang, Yuan Huixiong, Li Xia, Chen Ming, Peng Rui, Chen Siyu, Zou Xue, Yang Yuan, Long Hehua, Liu Zeying, Wang Teng, Guo Bing, Liu Lirong
Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
FASEB J. 2025 May 31;39(10):e70651. doi: 10.1096/fj.202402703R.
The protein lysine methyltransferase 2 (SMYD2) can affect cell proliferation, differentiation, and survival through methylation of its histone and non-histone substrates. SMYD2 has been shown to act as an oncogene to promote disease progression in a variety of cancer diseases, but its role in chronic kidney diseases (CKD) pathogenesis has not been fully elucidated. This study aims to investigate the effect of SMYD2 on cisplatin-induced CKD and its underlying mechanisms. In this study, we found that cisplatin caused severe renal injury in mice, which was accompanied by the up-regulation of SMYD2 expression. AZ505 treatment significantly down-regulated cisplatin-induced renal injury and fibrosis. It also alleviated renal apoptosis and inhibited the phosphorylation level of NF-κB p65. Conditional knockdown of Smyd2 achieved similar effects as AZ505. In renal tubular epithelial cells, inhibition or silencing of SMYD2 down-regulated cisplatin-induced apoptotic response, while overexpression of SMYD2 induced apoptotic response and activated NF-κB in response to the up-regulation of SMYD2 expression. Up-regulation of SMYD2 induced interaction and phosphorylation of SMYD2 and NF-κB p65, and inhibition of NF-κB activation further suppressed cisplatin-induced NF-κB activation and apoptosis. The present study suggests that up-regulation of SMYD2 expression in cisplatin-induced CKD may promote apoptosis of renal tubular epithelial cells and accelerate the process of renal injury through NF-κB activation. SMYD2 may serve as a potential target for effective CKD treatment.
蛋白质赖氨酸甲基转移酶2（SMYD2）可通过对其组蛋白和非组蛋白底物进行甲基化来影响细胞增殖、分化和存活。SMYD2已被证明在多种癌症疾病中作为癌基因促进疾病进展，但其在慢性肾脏病（CKD）发病机制中的作用尚未完全阐明。本研究旨在探讨SMYD2对顺铂诱导的CKD的影响及其潜在机制。在本研究中，我们发现顺铂可导致小鼠严重肾损伤，同时伴有SMYD2表达上调。AZ505处理可显著下调顺铂诱导的肾损伤和纤维化。它还减轻了肾细胞凋亡并抑制了NF-κB p65的磷酸化水平。条件性敲低Smyd2产生了与AZ505相似的效果。在肾小管上皮细胞中，抑制或沉默SMYD2可下调顺铂诱导的凋亡反应，而SMYD2的过表达则诱导凋亡反应并激活NF-κB以响应SMYD2表达的上调。SMYD2的上调诱导了SMYD2与NF-κB p65的相互作用和磷酸化，抑制NF-κB激活进一步抑制了顺铂诱导的NF-κB激活和凋亡。本研究表明，顺铂诱导的CKD中SMYD2表达上调可能通过NF-κB激活促进肾小管上皮细胞凋亡并加速肾损伤进程。SMYD2可能成为有效治疗CKD的潜在靶点。
