Xu Li-Nan, Sun Ying-Ying, Tan Yan-Feng, Zhou Xin-Yue, Xiang Tian-Chao, Fang Ye, Li Fei, Shen Qian, Xu Hong, Rao Jia
Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, China.
Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai 201100, China.
Cells. 2025 Jun 13;14(12):895. doi: 10.3390/cells14120895.
encodes an actin-binding protein involved in kidney development and has been associated with chronic kidney disease through genome-wide association studies. However, its regulatory role in proteinuric kidney diseases and its mechanistic contributions to podocyte homeostasis remain poorly defined. Here, we analyzed single-cell transcriptomic datasets and the Nephroseq database to delineate expression patterns in proteinuric kidney diseases. Using podocyte-specific knockout mice and an Adriamycin (ADR)-induced nephropathy mouse model, we demonstrated that glomerular , specifically in podocytes, was upregulated following ADR treatment during the acute injury phase but downregulated in chronic kidney disease. Clinically, the glomerular expression positively correlated with glomerular filtration rates in focal segmental glomerulosclerosis patients. Genetic ablation of in podocytes exacerbated ADR-induced proteinuria, diminished podocyte markers (nephrin, podocin, and WT1), and accelerated glomerulosclerosis. In vitro, deficiency impaired podocyte size and adhesion, concomitant with the downregulation of focal adhesion molecules (talin1, vinculin, and paxillin) and stress fiber regulators (synaptopodin and RhoA), as well as calpain activation and RhoA inactivation. Our findings reveal a critical role for in maintaining podocyte integrity and suggest its therapeutic potential in mitigating proteinuric kidney disease progression.
编码一种参与肾脏发育的肌动蛋白结合蛋白，并且通过全基因组关联研究已与慢性肾脏病相关联。然而，其在蛋白尿性肾脏疾病中的调节作用及其对足细胞稳态的机制性贡献仍不清楚。在此，我们分析了单细胞转录组数据集和Nephroseq数据库，以描绘蛋白尿性肾脏疾病中的表达模式。使用足细胞特异性敲除小鼠和阿霉素（ADR）诱导的肾病小鼠模型，我们证明在急性损伤期ADR治疗后肾小球（特别是在足细胞中）的表达上调，但在慢性肾脏病中下调。临床上，在局灶节段性肾小球硬化症患者中，肾小球的表达与肾小球滤过率呈正相关。足细胞中基因敲除加剧了ADR诱导的蛋白尿，减少了足细胞标志物（nephrin、podocin和WT1），并加速了肾小球硬化。在体外，缺乏会损害足细胞大小和黏附，同时伴随着黏着斑分子（talin1、vinculin和paxillin）和应力纤维调节因子（synaptopodin和RhoA）的下调，以及钙蛋白酶激活和RhoA失活。我们的研究结果揭示了在维持足细胞完整性中的关键作用，并表明其在减轻蛋白尿性肾脏疾病进展方面的治疗潜力。
