Zheng Jingwen, Wang Qian, Xu Kangjie, Ma Mingyue, Wang Zhengdong, Sun Zhenxiang, Yang Shuang, Wang Xinyue, Yan Nan, Duan Xiaoxu
Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China.
Department of Human Anatomy, Shenyang Medical College, Shenyang 110034, PR China.
Ecotoxicol Environ Saf. 2024 Dec;288:117385. doi: 10.1016/j.ecoenv.2024.117385. Epub 2024 Nov 23.
Fluoride is an essential trace element for human. Adequate levels of fluoride are crucial for maintaining skeletal growth, but excessive fluoride exposure entering the body can cause renal damage, including damaged renal tubules and impaired renal function. However, the mechanism on fluoride-induced kidney injury remains unclear. This study aimed to explore the immune-inflammatory imbalance induced by fluoride and its possible mechanism in the kidneys. Mice were exposed to sodium fluoride (NaF) (0, 25, 50 and 100 mg/L) for five months. The results showed that NaF increased the renal weight and renal index. The NaF-treated groups exhibited higher serum creatinine (Cre), blood urea nitrogen (BUN), albumin (ALB) total protein (TP) levels. Further, NaF increased reactive oxygen species (ROS) levels, lipid peroxidation (LPO) levels and malondialdehyde (MDA) level. Superoxide dismutase (SOD) activity was reduced and glutathione (GSH) activities were reduced in fluoride-treated group. NaF treatment also downregulated the nuclear factor E2-related factor (Nrf2) protein and its downstream enzymes heme oxygenase-1 (HO-1) and NAD(P)H: Quinone Oxidoreductase 1(NQO1) in the kidneys. Further, NaF shifted Th1/Th2 balance toward Th1 bias. Similarly, NaF exhibited increased macrophages and augmented M1 differentiation but suppressed M2 differentiation. The renal inflammatory response was also induced by fluoride via activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and increase of the pro-inflammatory factors tumour necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), interleukin-6 (IL-6) and interleukin-18 (IL-18). In addition, NaF treatment reduced the expression of the histone 2B lysine 12 crotonylation (H2BK12cr) and H4K8cr proteins as well as decreased the histone acetyltransferase P300 protein. NaF incresed the protein expression of histone decrotonylation enzyme sirtuin1 (sirt1) and histone deacetylase 3 (HDAC3) and upregulated HDAC2 protein. These findings demonstrate that fluoride exposure induces renal dysfunction and oxidative injury, affects M1/M2 polarization and Th1/Th2 differentiation, and promotes the inflammatory response via histone lysine crotonylation, ultimately resulting in nephrotoxicity.
氟是人体必需的微量元素。适量的氟对于维持骨骼生长至关重要，但过量的氟进入人体会导致肾脏损伤，包括肾小管受损和肾功能受损。然而，氟诱导肾脏损伤的机制仍不清楚。本研究旨在探讨氟诱导的免疫炎症失衡及其在肾脏中的可能机制。将小鼠暴露于氟化钠（NaF）（0、25、50和100mg/L）中五个月。结果表明，NaF增加了肾脏重量和肾脏指数。NaF处理组的血清肌酐（Cre）、血尿素氮（BUN）、白蛋白（ALB）、总蛋白（TP）水平较高。此外，NaF增加了活性氧（ROS）水平、脂质过氧化（LPO）水平和丙二醛（MDA）水平。氟处理组的超氧化物歧化酶（SOD）活性降低，谷胱甘肽（GSH）活性降低。NaF处理还下调了肾脏中核因子E2相关因子（Nrf2）蛋白及其下游酶血红素加氧酶-1（HO-1）和NAD（P）H：醌氧化还原酶1（NQO1）。此外，NaF使Th1/Th2平衡向Th1偏倚方向转变。同样，NaF使巨噬细胞增加，M1分化增强，但抑制M2分化。氟还通过激活含吡咯结构域的NOD样受体家族3（NLRP3）炎性小体和增加促炎因子肿瘤坏死因子-α（TNF-α）、转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）和白细胞介素-18（IL-18）诱导肾脏炎症反应。此外，NaF处理降低了组蛋白2B赖氨酸12巴豆酰化（H2BK12cr）和H4K8cr蛋白的表达以及组蛋白乙酰转移酶P300蛋白的表达。NaF增加了组蛋白去巴豆酰化酶沉默调节蛋白1（sirt1）和组蛋白脱乙酰酶3（HDAC3）的蛋白表达，并上调了HDAC2蛋白。这些发现表明，氟暴露会导致肾功能障碍和氧化损伤，影响M1/M2极化和Th1/Th2分化，并通过组蛋白赖氨酸巴豆酰化促进炎症反应，最终导致肾毒性。
