Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.

局灶节段性肾小球硬化症（FSGS）是肾病综合征的主要原因，其特征是足细胞损伤。鉴于对非糖尿病肾小球硬化的病理生理学知之甚少，并且缺乏预防肾小球疾病的靶向治疗，我们决定研究紧密连接蛋白claudin-1和组蛋白脱乙酰酶sirtuin-1（SIRT1），已知它们与足细胞有关受伤。为此，我们首先检查了诊断为非糖尿病 FSGS 的患者肾活检中 SIRT1、claudin-1 和 podocin 的表达，发现肾小球claudin-1 的上调伴随着肾小球 SIRT1 和 podocin 水平的显着降低。由此，我们研究了 SIRT1 小分子激活剂 SRT1720 是否可以在阿霉素 (ADR) 诱导的肾病动物模型中延迟 FSGS 的发作；在 ADR + SRT1720 组中，使用 SRT1720 治疗 14 天可减轻肾小球硬化进展和蛋白尿，防止转录因子 Wilms 肿瘤 1 (WT1) 下调并增加肾小球 Claudin-1。因此，我们评估了 ADR 和/或 SRT1720 在培养的小鼠足细胞中的作用。结果显示，30 分钟后，ADR [1 µM] 引发claudin-1 表达增加，并且用 SRT1720 [5 µM] 预处理足细胞可减弱这种效应。 ADR [1 µM] 还导致这些细胞中 SIRT1 和claudin-1 定位的变化，这可能与足细胞损伤有关。尽管使用 SRT1720 等特异性激动剂对肾小球功能有一些益处，但其潜在机制仍需要进一步探索用于治疗用途。综上所述，我们的数据表明 SIRT1 和claudin-1 与非糖尿病 FSGS 的病理生理学相关。