Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy
Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy
复制标题
Caspase-11/4和gasdermin D介导的细胞焦亡导致小鼠糖尿病肾病足细胞损伤
DOI：
10.1038/s41401-020-00525-z
复制
发表时间：
2020-09-23
影响因子：
8.2
通讯作者：
Lu, Li-min
中科院分区：
文献类型：
--
作者：
Cheng, Qian;Pan, Jing;Lu, Li-min
糖尿病肾病（DN）的特点是无菌性炎症，伴有肾固有实质细胞的持续损伤和损失。足细胞是 DN 早期重要的损伤靶点。足细胞的损伤和丢失与蛋白尿密切相关，蛋白尿是DN肾损伤的早期症状。然而，DN 足细胞损伤和死亡的确切机制仍不清楚。在这项研究中，我们研究了焦亡（一种新发现的细胞死亡途径）是否与 DN 有关。糖尿病小鼠是通过高脂肪饮食/STZ注射产生的。我们发现足细胞中caspase-11和gasdermin D裂解（GSDMD-N）的表达水平显着升高，伴随着足细胞制造者nephrin和podocin的表达减少，足细胞足突的丢失和融合，炎性细胞因子NF-κB、IL-1β和IL-18增加，巨噬细胞浸润，肾小球基质扩张以及尿白蛋白与肌酐比值（UACR）增加。糖尿病小鼠的所有这些变化都因 caspase-11 或 GSDMD 敲除而减弱。用高葡萄糖 (30 mM) 处理培养的人和小鼠足细胞，显着增加 caspase-11 或 caspase-4（人 caspase-11 的同源物）、GSDMD-N、NF-κ B、IL-1 beta 和 IL-18 的表达水平，并降低去氧肾上腺素和足多蛋白的表达。 caspase-4 或 siRNA 敲低 GSDMD 都会显着减弱这些变化。总之，我们的结果表明 caspase-11/4 和 GSDMD 介导的细胞焦亡被激活并参与高血糖条件下足细胞的丢失和 DN 的发展。
Diabetic nephropathy (DN) is characterized by sterile inflammation with continuous injury and loss of renal inherent parenchyma cells. Podocyte is an essential early injury target in DN. The injury and loss of podocytes are closely associated with proteinuria, the early symptom of renal injury in DN. However, the exact mechanism for podocyte injury and death in DN remains ambiguous. In this study we investigated whether pyroptosis, a newly discovered cell death pathway was involved in DN. Diabetic mice were generated by high-fat diet/STZ injections. We showed that the expression levels of caspase-11 and cleavage of gasdermin D (GSDMD-N) in podocytes were significantly elevated, accompanied by reduced expression of podocyte makers nephrin and podocin, loss and fusion in podocyte foot processes, increased inflammatory cytokines NF-kappa B, IL-1 beta, and IL-18, macrophage infiltration, glomerular matrix expansion and increased urinary albumin to creatinine ratio (UACR). All these changes in diabetic mice were blunted by knockout of caspase-11 or GSDMD. Cultured human and mouse podocytes were treated with high glucose (30 mM), which significantly increased the expression levels of caspase-11 or caspase-4 (the homolog of caspase-11 in human), GSDMD-N, NF-kappa B, IL-1 beta, and IL-18, and decreased the expression of nephrin and podocin. Either caspase-4 or GSDMD knockdown by siRNA significantly blunted these changes. In summary, our results demonstrate that caspase-11/4 and GSDMD-mediated pyroptosis is activated and involved in podocyte loss under hyperglycemia condition and the development of DN.