四川大学马良等研究人员合作发现，抑制染色体结构域Y样（CDYL）可通过调节肾小管脓毒症改善小鼠急性肾损伤。2024年7月23日，《中国药理学报》在线发表了这一成果。

研究人员首次探索了一种新型的Chromodomain Y-like（CDYL）抑制剂——苯并[d]噁唑-2(3H)-酮衍生物（化合物D03），其具有较高的效力和选择性（K_D=0.5μM）。研究人员揭示了CDYL在顺铂（Cis）、脂多糖（LPS）和缺血/再灌注损伤（IRI）诱导的急性肾损伤（AKI）小鼠模型中的表达情况。

通过对肾脏样本进行RNA测序和差异分析，研究人员发现CDYL在AKI患者和小鼠受损肾脏中的肾小管中异常高表达。在顺铂诱导的AKI小鼠中，CDYL的过表达通过调控脂肪酸结合蛋白4（FABP4）介导的活性氧生成，加剧了肾小管损伤和细胞焦亡。

使用化合物D03（2.5mg/kg每天，腹腔注射）治疗顺铂诱导的AKI小鼠，有效减轻了肾功能不全、病理损伤和肾小管细胞焦亡，而对肝肾功能和其他组织没有副作用。总之，该研究首次探讨了CDYL在肾损伤中对肾小管上皮细胞焦亡的作用，并证实抑制CDYL可能是一种对抗AKI的有前景的治疗策略。

研究人员表示，AKI是一种常见疾病，但缺乏有效的药物治疗。CDYL是一种染色体结构域蛋白，已被证明在常染色体显性多囊肾病的转录调控中起作用。

附：英文原文

Title: Chromodomain Y‐like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis

Author: Xiang, Ting, Li, Ling-zhi, Li, Jin-xi, Chen, Xin-yun, Guo, Fan, Liu, Jing, Wu, Yi-ting, Lin, Lin, Xu, Rui-han, Wang, Hui-ping, Ma, Liang, Fu, Ping

Issue&Volume: 2024-07-23

Abstract: Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y‐like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD=0.5μM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5mg·kg1·d1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

DOI: 10.1038/s41401-024-01345-1

Source: https://www.nature.com/articles/s41401-024-01345-1