Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain–containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

中文翻译：

---

NLRP3 和 STING 在 APOL1 相关足细胞病中的关键作用

载脂蛋白 L1 ( APOL1 ) 的编码变体，称为 G1 和 G2，可以解释非裔美国人大多数过度的肾病风险；然而，对 APOL1 诱导的肾功能障碍的分子途径仍知之甚少。在这里，我们报道了 G2 APOL1在Nphs1rtTA/TRE-G2APOL1 ( G2APOL1 ) 小鼠足细胞中的表达导致细胞溶质核苷酸传感器、干扰素基因刺激物 ( STING ) 和 NLR 家族 pyrin 结构域的早期激活——包含 3 ( NLRP3 ) 炎性小体。高危APOL1基因型患者足细胞中 STING 和 NLRP3 表达增加，APOL1表达增加与 caspase-1 和 gasdermin D ( GSDMD ) 水平相关。为了证明NLRP3和STING在APOL1相关肾脏疾病中的作用，我们生成了具有 G2 APOL1风险变异和Nlrp3 ( G2APOL1 / Nlrp3 KO)、Gsdmd ( G2APOL1 / Gsdmd KO) 和STING ( G2APOL1 / STING KO）。与G2APOL1相比，基因敲除小鼠的白蛋白尿、氮质血症和肾纤维化显着减少老鼠。为了评估靶向NLRP3、GSDMD和STING的治疗潜力，我们分别用 NLRP3、GSDMD 和 STING 的强效选择性抑制剂 MCC950、双硫仑和 C176 治疗小鼠。用 MCC950、双硫仑和 C176 治疗的G2APOL1小鼠显示出较低的白蛋白尿和改善的肾功能，即使在出现白蛋白尿后开始抑制剂治疗也是如此。