Xiao An, Chen Xiaoer, Ma Jingyi, Chen Xiaomei, Long Tantan, Ma Yuanyuan, Chen Qingzhou, Su Zhiyuan, Hu Zheng, Xie Liling, Zhang Lei, Zhu Fengxin, Nie Jing
National Key Laboratory for Prevention and Treatment of Multi-organ Injury, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
National Key Laboratory for Prevention and Treatment of Multi-organ Injury, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Biobank of Peking University First Hospital, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Peking University, Beijing, China.
Kidney Int. 2025 Jul;108(1):74-89. doi: 10.1016/j.kint.2025.03.021. Epub 2025 Apr 22.
Chronic Kidney Disease (CKD) is marked by progressive tubulointerstitial fibrosis (TIF), a pathological feature insufficiently addressed by existing therapies.
To identify drugs with potential to halt TIF progression, we constructed a TIF-specific gene expression signature using published human CKD kidney transcriptome data and employed the small molecule perturbant library LINCS L1000 database for a high-throughput screening of compounds capable of reversing the expression of TIF-related genes.
Narciclasine, a natural compound derived from the Narcissus (amaryllis) plant, was identified as a top compound which significantly reversed the gene expression signature of TIF. Administration of narciclasine not only significantly prevented inflammation and fibrotic lesions induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury but also delayed the progression of established TIF induced by unilateral ureteral obstruction. Furthermore, in the 5/6 nephrectomy-induced CKD model, narciclasine significantly lowered serum creatinine, reduced proteinuria, and alleviated TIF and inflammation.
Mechanistically, narciclasine reversed the failed-repair phenotype of tubular epithelial cells and inhibited fibroblasts proliferation and activation, at least partially via inhibiting the activation of NF-κB signaling. Our findings suggest that narciclasine should be further investigated as a promising drug candidate to attenuate CKD.
慢性肾脏病（CKD）的特征是进行性肾小管间质纤维化（TIF），这是现有疗法尚未充分解决的病理特征。
为了鉴定具有阻止TIF进展潜力的药物，我们利用已发表的人类CKD肾脏转录组数据构建了TIF特异性基因表达特征，并使用小分子干扰文库LINCS L1000数据库对能够逆转TIF相关基因表达的化合物进行高通量筛选。
水仙环素，一种从水仙（石蒜科）植物中提取的天然化合物，被鉴定为一种顶级化合物，它能显著逆转TIF的基因表达特征。给予水仙环素不仅能显著预防单侧输尿管梗阻和单侧缺血再灌注损伤诱导的炎症和纤维化病变，还能延缓单侧输尿管梗阻诱导的已建立的TIF的进展。此外，在5/6肾切除诱导的CKD模型中，水仙环素显著降低血清肌酐，减少蛋白尿，并减轻TIF和炎症。
从机制上讲，水仙环素至少部分通过抑制NF-κB信号通路的激活，逆转了肾小管上皮细胞的修复失败表型，并抑制了成纤维细胞的增殖和激活。我们的研究结果表明，水仙环素作为一种有前景的减轻CKD的候选药物，应进一步研究。
