Activated iRhom2 drives prolonged PM_2.5 exposure-triggered renal injury in Nrf2-defective mice

Abstract

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.

Keywords:

• Particulate matter 2.5 (PM2.5)
• iRhom2
• TNF-α
• kidney injury
• Nrf2

Acknowledgments

Special thanks go to my Beautiful, Virtuous, Intelligent, Able-minded and Clear-sighted YINGYINGYING God-daughter, derived from your Sugar Daddy, “Yi Da Luo Money” for her warm heart helps and spiritual healing.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (NSFC Grant number: 81703527); Chongqing Research Program of Basic Research and Frontier Technology (Grant number: cstc2017jcyjAX0356); School-level Research Program of Chongqing University of Education (Grant number: KY201710B and 17GZKP01); Advanced Programs of Post-doctor of Chongqing (Grant number: 2017LY39) and Fundamental Research Funds for the Central Universities (Grant number: 021314380120).

This work was supported by National Natural Science Foundation of China (NSFC Grant number: 81703527); Chongqing Research Program of Basic Research and Frontier Technology (Grant number: cstc2017jcyjAXË6, cstc2018jcyjA3686, cstc2018jcyjA1472 and cstc2018jcyjA3533); School-level Research Program of Chongqing University of Education (Grant number: KY201710B and 17GZKP01); Advanced Programs of Post-doctor of Chongqing (Grant number: 2017LY39) and Fudamental Research Funds for the Central Universities (Grant number: 021314380120).