Research suggests that particulate matter (PM_2.5) is a predisposing factor for metabolic syndrome-related systemic inflammation and oxidative stress injury. TNF-α as a major pro-inflammatory cytokine was confirmed to participate in various diseases. Inactive rhomboid protein 2 (iRhom2) was recently determined as a necessary regulator for shedding of TNF-α in immune cells. Importantly, kidney-resident macrophages are critical to inflammation-associated chronic renal injury. Podocyte injury can be induced by stimulants and give rise to nephritis, but how iRhom2 contributes to PM_2.5-induced renal injury is unclear. Thus, we studied whether PM_2.5 causes renal injury and characterized iRhom2 with respect to TNF-α release in mice macrophages and renal tissues in long-term PM_2.5-exposed mouse models. After long-term PM_2.5 exposures, renal injury was confirmed via inflammatory cytokine, chemokine expression, and reduced antioxidant activity. Patients with kidney-related diseases had increased TNF-α, which may contribute to renal injury. We observed up-regulation of serum creatinine, serum urea nitrogen, kidney injury molecule 1, uric acid, TNF-α, MDA, H₂O_2, and O₂^– in PM_2.5-treated mice, which was greater than that found in Nrf2^−/− mice. Meanwhile, increases in metabolic disorder-associated indicators were involved in PM_2.5-induced nephritis. In vitro, kidney-resident macrophages were observed to be critical to renal inflammatory infiltration and function loss via regulation of iRhom2/TACE/TNF-α signaling, and suppression of Nrf2-associated anti-oxidant response. PM_2.5 exposure led to renal injury partly by inflammation-mediated podocyte injury. Reduced SOD1, SOD2, Nrf2 activation, and increased XO, NF-κB activity, TACE, iNOS, IL-1β, TNF-α, IL-6, MIP-1α, Emr-1, MCP-1, and Cxcr4, were also noted. Long-term PM_2.5 exposure causes chronic renal injury by up-regulation of iRhom2/TACE/TNF-α axis in kidney-resident macrophages. Overexpression of TNF-α derived from macrophages causes podocyte injury and kidney function loss. Thus, PM_2.5 toxicities are related to exposure duration and iRhom2 may be a potential therapeutic renal target.

中文翻译：

---

激活的iRhom2在Nrf2缺陷小鼠中驱动PM _2.5暴露触发的长时间肾脏损伤

研究表明，颗粒物（PM _2.5）是与代谢综合征相关的全身性炎症和氧化应激损伤的诱因。TNF-α作为主要的促炎细胞因子被证实参与多种疾病。最近，非活性菱形蛋白2（iRhom2）被确定为免疫细胞中TNF-α脱落的必要调节剂。重要的是，驻留肾脏的巨噬细胞对于与炎症相关的慢性肾脏损伤至关重要。刺激物可诱发足细胞损伤并引起肾炎，但目前尚不清楚iRhom2如何引起PM _2.5诱导的肾损伤。因此，我们研究了PM _2.5是否在长期暴露于PM _2.5的小鼠模型中，其可引起肾脏损伤并针对小鼠巨噬细胞和肾脏组织中的TNF-α释放对iRhom2进行了表征。长期暴露于PM _2.5后，通过炎症性细胞因子，趋化因子表达和降低的抗氧化活性证实了肾损伤。肾脏相关疾病患者的TNF-α升高，可能导致肾脏损伤。我们观察到上调血清肌酸酐，血清尿素氮，肾损伤分子-1，尿酸，TNF-α，MDA，H ₂ ö _2，和O ₂ ^-在PM _2.5处理的小鼠，比在所发现较大Nrf2 ^-/-老鼠。同时，与代谢紊乱相关的指标的增加与PM _2.5诱发的肾炎有关。在体外，通过调节iRhom2 / TACE /TNF-α信号传导和抑制Nrf2相关的抗氧化反应，观察到肾驻留型巨噬细胞对肾炎性浸润和功能丧失至关重要。PM _2.5暴露部分地由炎症介导的足细胞损伤导致肾损伤。还降低了SOD1，SOD2，Nrf2的活化并提高了XO，NF-κB活性，TACE，iNOS，IL-1β，TNF-α，IL-6，MIP-1α，Emr-1，MCP-1和Cxcr4。著名的。长期PM _2.5暴露会通过驻留肾脏的巨噬细胞中iRhom2 / TACE /TNF-α轴的上调而引起慢性肾脏损伤。源自巨噬细胞的TNF-α的过表达导致足细胞损伤和肾功能丧失。因此，PM _2.5毒性与暴露时间有关，iRhom2可能是潜在的治疗性肾脏靶标。