Lead (Pb) is one of the most prevalent heavy metals found in the environment [1], [2]. and is widely used in numerous industrial products such as batteries, pigments, and metal plating [3]. It enters the food chain mainly through polluted air, soil, water, and food in many countries [4]. Pb is one of the most common sources of heavy metal exposure, contributing to tissue and organ damage in the human body [5]. Moreover, it can adversely affect various bodily functions, inducing gastrointestinal, neurological, reproductive, hematological, and immunological effects [6]. Pb poisoning has emerged as a crucial health risk for both humans and animals, particularly during industrialization in China, with children being especially vulnerable [7]. This exposure causes devastating damage not only to brain development but also to kidney function [8]. Heavy metal poisoning has detrimental effects on neurodevelopment[9] and behavioral impairments during early childhood [10]. Even low concentrations of Pb in the blood can result in the reduction of intelligence quotient [11]. In addition, the kidney, being a pivotal metabolic organ, is highly sensitive to Pb poisoning, alongside brain [12]. Studies on Pb poisoning have suggested that it is associated with a wide range of kidney biological alterations, including histopathological changes and oxidative injury [13], [14].

At present, chelating therapy, such as calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), is one of the most effective therapeutic methods for Pb accumulation, promoting its excretion in vivo[15]. Unfortunately, chelating drugs cannot be used to treat Pb poisoning due to their numerous side effects and failure to ameliorate Pb-induced renal injury. Moreover, exceeding the maximum daily intake of these drugs may increase the risk of death. Additionally, chelation therapy may remove essential heavy metals from the body [16]. Thus, an urgent need exists to identify highly effective, safe, and low-toxicity drugs for the treatment of Pb poisoning.

As an essential nutritional factor, selenium (Se) could reverse spontaneous and secondary pathophysiological changes caused by oxidative stress [17]. Meanwhile, it is a key component of most selenoproteins, including glutathione peroxidases (GSH-Px), heme oxygenase-1 (HO-1) and thioredoxin reductases [18]. These selenoproteins play crucial roles in antioxidant defense, immunity, and detoxification functions [19]. Moreover, Se possesses a strong affinity for metal elements and may diminish the toxicity of heavy metals, such as Pb [20], aluminum [21] and cadmium [22]. Furthermore, antioxidants have been suggested to improve the efficacy and survival rate of treatments aimed at alleviating Pb-induced toxicity [23]. Se has been highly advocated as a food additive for disease prevention and treatment due to its ability to prevent certain diseases and remove reactive oxygen species (ROS)[24]. Moreover, the studies have indicated that Se-containing peptides protect against Pb-induced oxidative stress in NCTC1469 hepatocytes by regulating the Kelch-like ECH-associated protein 1 (KEAP1)/ Nuclear factor (erythroid-derived-2)-related factor 2 (NRF2) pathway [25]. Further, the NRF2 pathway may be related to the antagonistic effect of Se on Pb-induced apoptosis and oxidative stress in sheep Leydig cells [26].

In a previous study, we found that Se has antioxidant properties and Pb ion-chelating activities. Nevertheless, whether Se exerts a similar protective effect on Pb-induced kidney injury by modulating NRF2 expression remains unknown. In the present study, we investigate the protective effects of Se against Pb-induced renal oxidative injury in human renal tubular epithelial (HK-2) cells and weaning rats. Our findings demonstrate that Se ameliorated Pb-induced nephrotoxicity by reducing oxidative stress in vivo and in vitro.