Podocytes can undergo PANoptosis (apoptosis, pyroptosis, and necroptosis). Diabetic kidney disease (DKD) is the leading cause of kidney failure, and podocyte loss is a major event leading to the progression of DKD. Here, we compared single cell RNA sequencing (scRNA-seq) data between three normal and three DKD human kidney samples and found a significant increase of TNFSF10 and TNFRSF10B expression in podocytes of patients with DKD. Tumor necrosis factor (TNF)-related apoptosis–inducing ligand (TRAIL), coded by TNFSF10, belongs to the TNF superfamily members and TNFRSF10B codes for death receptor 5 (DR5). We confirmed that expression of TRAIL and DR5 increased in podocytes of patients with DKD and correlated with the severity of DKD. In vitro, TNF-α stimulated TRAIL and DR5 expression in cultured human podocytes. Silence of TRAIL or DR5 by small interfering RNA alleviated TNF-α-stimulated podocytes PANoptosis, while overexpression of TRAIL, treatment with recombinant human TRAIL (rh-TRAIL) or the DR5 activator (Bioymifi) enhanced podocytes PANoptosis. In vivo, podocyte-specific deletion of TNFSF10 or TNFRSF10B alleviated podocyte and glomerular injury in high fat diet and streptozotocin-induced obese diabetic mice and was associated with decreased podocyte PANoptosis. Conversely, the induction of TNFSF10 overexpression specifically in podocytes exacerbated albuminuria and kidney injury in diabetic mice with increased podocyte PANoptosis. Additionally, administration of soluble DR5-Fc, an inhibitor of DR5, resulted in a marked reduction in albuminuria and glomerular injury in BTBR ob/ob mice. Our findings suggest a critical autocrine role of TRAIL/DR5 in inducing podocyte injury in DKD via activation of PANoptosis.

中文翻译：

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TRAIL 在糖尿病肾病中通过死亡受体 5 诱导足细胞泛细胞凋亡


足细胞可以经历 PANoptosis（细胞凋亡、焦亡和坏死性凋亡）。糖尿病肾病 （DKD） 是肾功能衰竭的主要原因，足细胞丢失是导致 DKD 进展的主要事件。在这里，我们比较了 3 个正常和 3 个 DKD 人肾样本之间的单细胞 RNA 测序 （scRNA-seq） 数据，发现 DKD 患者足细胞中 TNFSF10 和 TNFRSF10B 表达显著增加。由 TNFSF10 编码的肿瘤坏死因子 （TNF） 相关凋亡诱导配体 （TRAIL） 属于 TNF 超家族成员，TNFRSF10B死亡受体 5 （DR5） 编码。我们证实 TRAIL 和 DR5 的表达在 DKD 患者的足细胞中增加，并与 DKD 的严重程度相关。在 体外，TNF-α 刺激培养的人足细胞中 TRAIL 和 DR5 的表达。通过小干扰 RNA 沉默 TRAIL 或 DR5 减轻了 TNF α刺激的足细胞 PANoptosis，而 TRAIL 的过表达，用重组人 TRAIL （rh-TRAIL） 或 DR5 激活剂 （Bioymifi） 处理增强了足细胞 PANoptosis。在 体内，TNFSF10 或 TNFRSF10B 的足细胞特异性缺失减轻了高脂饮食和链脲佐菌素诱导的肥胖糖尿病小鼠的足细胞和肾小球损伤，并且与足细胞细胞凋亡减少有关。相反，在足细胞中特异性地诱导 TNFSF10 过表达加剧了足细胞 PANoptosis增加的糖尿病小鼠的白蛋白尿和肾损伤。此外，可溶性 DR5-Fc（一种 DR5 抑制剂）的给药导致 BTBR ob/ob 小鼠的白蛋白尿和肾小球损伤显着减少。我们的研究结果表明，TRAIL/DR5 在通过激活 PANoptosis诱导 DKD 足细胞损伤中具有关键的自分泌作用。