title: Osthole mitigates progressive IgA nephropathy by inhibiting reactive oxygen species generation and NF-κB/NLRP3 pathway.
abstract: Renal reactive oxygen species (ROS) and mononuclear leukocyte infiltration are involved in the progressive stage (exacerbation) of IgA nephropathy (IgAN), which is characterized by glomerular proliferation and renal inflammation. The identification of the mechanism responsible for this critical stage of IgAN and the development of a therapeutic strategy remain a challenge. Osthole is a pure compound isolated from Cnidiummonnieri (L.) Cusson seeds, which are used as a traditional Chinese medicine, and is anti-inflammatory, anti-apoptotic, and anti-fibrotic both in vitro and in vivo. Recently, we showed that osthole acts as an anti-inflammatory agent by reducing nuclear factor-kappa B (NF-κB) activation in and ROS release by activated macrophages. In this study, we examined whether osthole could prevent the progression of IgAN using a progressive IgAN (Prg-IgAN) model in mice. Our results showed that osthole administration resulted in prevention of albuminuria, improved renal function, and blocking of renal progressive lesions, including glomerular proliferation, glomerular sclerosis, and periglomerular mononuclear leukocyte infiltration. These findings were associated with (1) reduced renal superoxide anion levels and increased Nrf2 nuclear translocation, (2) inhibited renal activation of NF-κB and the NLRP3 inflammasome, (3) decreased renal MCP-1 expression and mononuclear leukocyte infiltration, (4) inhibited ROS production and NLRP3 inflammasome activation in cultured, activated macrophages, and (5) inhibited ROS production and MCP-1 protein levels in cultured, activated mesangial cells. The results suggest that osthole exerts its reno-protective effects on the progression of IgAN by inhibiting ROS production and activation of NF-κB and the NLRP3 inflammasome in the kidney. Our data also confirm that ROS generation and activation of NF-κB and the NLRP3 inflammasome are crucial mechanistic events involved in the progression of the renal disorder.
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, Republic of China.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.forename: Shun-Min
authors.initials: SM
authors.lastname: Yang
authors.forename: Tzu-Yang
authors.initials: TY
authors.lastname: Kao
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Tsai
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: Louis Kuoping
authors.initials: LK
authors.lastname: Chao
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D003374:Coumarins / Q000627:therapeutic use*; D005922:Glomerulonephritis, IGA / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D003374:Coumarins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D020169:Caspases; C046627:osthol