南京医科大学Ai-qing Zhang等研究人员合作发现，tRF3-IleAAT通过靶向ZNF281和抑制铁死亡反应减少糖尿病肾病小鼠细胞外基质的合成。2024年1月29日，《中国药理学报》杂志在线发表了这项成果。

研究人员表示，已经证实，间质细胞中细胞外基质（ECM）的合成是糖尿病肾病（DKD）的主要决定因素。tRF3-IleAAT是由核酸酶在tRNA特异性位点产生的tRNA衍生片段（tRF），它在糖尿病患者和DKD患者的血清中表达不同。

研究人员探讨了tRF在DKD中的潜在作用。研究人员将12周的db/db小鼠作为DKD模型。这些小鼠表现出明显的肾功能障碍，tRF3-IleAAT的表达明显减少，肾组织中的铁死亡和ECM合成增加。在高糖处理的小鼠肾小球系膜细胞中也观察到了tRF3-IleAAT的表达减少。研究人员给12周龄以上的小鼠注射ferrostatin-1（1mg/kg，每两天一次，静脉注射），连续注射8周后发现，抑制铁死亡反应的发生可显著改善肾功能、减轻肾脏纤维化并减少胶原沉积。通过尾静脉注射携带tRF3-IleAAT的AAV，过表达tRF3-IleAAT可明显抑制DKD模型小鼠的铁死亡和ECM合成。

此外，研究人员还发现在DKD模型中，tRF3-IleAAT的下游靶基因锌指蛋白281（ZNF281）的表达显著升高，但受tRF3-IleAAT的负调控。在高糖处理的系膜细胞中，敲除ZNF281可抑制铁死亡和ECM合成。研究人员证明了tRF3-IleAAT与ZNF281的3'UTR的靶向结合。总之，tRF3-IleAAT通过靶向ZNF281来抑制铁死亡，从而减轻DKD模型中ECM的合成，这表明tRF3-IleAAT可能是一种有吸引力的DKD治疗靶点。

附：英文原文

Title: tRF3-IleAAT reduced extracellular matrix synthesis in diabetic kidney disease mice by targeting ZNF281 and inhibiting ferroptosis

Author: Qiao, Yun-yang, Ji, Jia-ling, Hou, Wei-ling, Qu, Gao-ting, Li, Shan-wen, Li, Xing-yue, Jin, Ran, Li, Yin-fang, Shi, Hui-min, Zhang, Ai-qing

Issue&Volume: 2024-01-29

Abstract: It is well established that the synthesis of extracellular matrix (ECM) in mesangial cells is a major determinant of diabetic kidney disease (DKD). Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression. tRF3-IleAAT is a tRNA-derived fragment (tRF) produced by nucleases at tRNA-specific sites, which is differentially expressed in the sera of patients with diabetes mellitus and DKD. In this study we investigated the potential roles of tRFs in DKD. Db/db mice at 12 weeks were adapted as a DKD model. The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-IleAAT and increased ferroptosis and ECM synthesis in the kidney tissues. The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells. We administered ferrostatin-1 (1mg/kg, once every two days, i.p.) to the mice from the age of 12 weeks for 8 weeks, and found that inhibition of the onset of ferroptosis significantly improved renal function, attenuated renal fibrosis and reduced collagen deposition. Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice. Furthermore, we found that the expression of zinc finger protein 281 (ZNF281), a downstream target gene of tRF3-IleAAT, was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT. In high glucose-treated mesangial cells, knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis. We demonstrated the targeted binding of tRF3-IleAAT to the 3’UTR of ZNF281. In conclusion, tRF3-IleAAT inhibits ferroptosis by targeting ZNF281, resulting in the mitigation of ECM synthesis in DKD models, suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.

DOI: 10.1038/s41401-024-01228-5

Source: https://www.nature.com/articles/s41401-024-01228-5