Ecotoxicology and Environmental Safety (Mar 2023)
Ferroptosis contribute to neonicotinoid imidacloprid-evoked pyroptosis by activating the HMGB1-RAGE/TLR4-NF-κB signaling pathway
Abstract
Imidacloprid (IMI) is among the common neonicotinoid insecticides used in agriculture worldwide, posing a potential toxic threat to non-target animals and humans. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of renal diseases. However, it remains unclear whether ferroptosis is involved in IMI-induced nephrotoxicity. In the present study, we investigated the potential pathogenic role of ferroptosis in IMI-induced kidney damage in vivo. Transmission electron microscopy (TEM) showed that the mitochondrial crest of kidney cells significantly decreased following IMI exposure. Moreover, IMI exposure triggered ferroptosis and lipid peroxidation in the kidney. We confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant capability was negatively correlated with the ferroptosis induced by IMI exposure. Importantly, we verified that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-driven inflammation occurred in the kidneys following IMI exposure, but pretreatment with the ferroptosis inhibitor ferrostatin (Fer-1) blocked this phenomenon. Additionally, IMI exposure induced F4/80+ macrophages to accumulated in the proximal tubules of the kidneys, and also increased the protein expression of high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), receptor for advanced glycation end products (TLR4), and nuclear factor kappa-B (NF-κB). In contrast, inhibition of ferroptosis by Fer-1 blocked IMI-induced NLRP3 inflammasome activation, F4/80 positive macrophages, and the HMGB1-RAGE/TLR4 signaling pathway. To the best of our knowledge, this is the first study to reveal that IMI stress can induce Nrf2 inactivation, thereby triggering ferroptosis, causing an initial wave of death, and activating HMGB1-RAGE/TLR4 signaling, which promotes pyroptosis that perpetuates kidney dysfunction.