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.

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome

“…It has been reported that NF-κB activation is associated with NLRP3 inflammasome formation [81,87,88]; however, the crosstalk between NF-κB pathway and NLRP3 inflammasome is still obscure. According to previous studies, we suppose that the involved mechanism may be partial due to NF-κB activation increasing the gene transcription of NLRP3, which contributes to NLRP3 inflammasome formation [89,90].…”

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

“…Furthermore, we found that imperatorin directly activated Ca 2+ flux in human neutrophils and transfected FPR1 HL-60 cells and that bergapten did not inhibit Ca 2+ mobilization in f MLF-stimulated human neutrophils and FPR1 HL-60 cells (Table 2), thus excluding these compounds as possible FPR1 antagonists. It should be noted that osthol is a known plant-derived compound with anti-inflammatory activity and a broad spectrum of molecular targets [109, 110]. Osthol had a weak inhibitory effect on f MLF-induced HNE release [94].…”

Association Between <b><i>IFN-γ</i></b> Gene Polymorphisms and IgA Nephropathy in a Chinese Han Population

“…Silva et al demonstrated that the over-expression of NF-κB was correlated with poor prognosis in patients with IgAN [30]. Activation of NF-κB is also crucial in the progression of the renal pathology of IgAN [31]. In addition, the DNA sequences containing the rs2430561 and rs1861494 are the specific binding sites for the NF-κB transcription factor.…”