科研之友
微信
新浪微博
Facebook
分享链接
摘要
Research suggests that particulate matter (PM2.5) is a predisposing factor for metabolic syndrome-related systemic inflammation and oxidative stress injury. TNF-alpha 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-alpha 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 PM2.5-induced renal injury is unclear. Thus, we studied whether PM2.5 causes renal injury and characterized iRhom2 with respect to TNF-alpha release in mice macrophages and renal tissues in long-term PM2.5-exposed mouse models. After long-term PM2.5 exposures, renal injury was confirmed via inflammatory cytokine, chemokine expression, and reduced antioxidant activity. Patients with kidney-related diseases had increased TNF-alpha, which may contribute to renal injury. We observed up-regulation of serum creatinine, serum urea nitrogen, kidney injury molecule 1, uric acid, TNF-alpha, MDA, H2O2, and O-2(-) in PM2.5-treated mice, which was greater than that found in Nrf2(-/-) mice. Meanwhile, increases in metabolic disorder-associated indicators were involved in PM2.5-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-alpha signaling, and suppression of Nrf2-associated anti-oxidant response. PM2.5 exposure led to renal injury partly by inflammation-mediated podocyte injury. Reduced SOD1, SOD2, Nrf2 activation, and increased XO, NF-kappa B activity, TACE, iNOS, IL-1 beta, TNF-alpha, IL-6, MIP-1 alpha, Emr-1, MCP-1, and Cxcr4, were also noted. Long-term PM2.5 exposure causes chronic renal injury by up-regulation of iRhom2/TACE/TNF-alpha axis in kidney-resident macrophages. Overexpression of TNF-alpha derived from macrophages causes podocyte injury and kidney function loss. Thus, PM2.5 toxicities are related to exposure duration and iRhom2 may be a potential therapeutic renal target.
