The role of PI3K/AKT pathway in the effect of naringin on lead acetate-induced nephrotoxicity

Lead (Pb) is a toxic heavy metal that is widespread in the environment and extensively used in industrial settings. By accumulating in bones and teeth, chronic exposure leads to multi-organ dysfunction, primarily affecting the nervous system and kidneys. Naringin (N) is a flavonoid predominantly found in citrus fruits with well-known antioxidant properties. This study aimed to evaluate the protective effect of N against Pb-induced kidney injury and its relationship with the PI3K/Akt signaling pathway, based on gene expression levels, antioxidant defense systems, biochemical indicators, element levels, and histopathological findings. Wistar rats were assigned to control, N, lead acetate (PbAc), and PbAc + N groups. Kidney tissues were collected for elemental analysis, enzymatic and non-enzymatic activity assays, PI3K and Akt1 gene expression, histopathological and immunohistochemical examinations, while blood samples were obtained intracardially for biochemical parameters. In the PbAc group, creatinine, urea, Mn, Pb, and Mg levels, as well as AChE and GST activities, MDA levels, and PI3K/Akt1 expression increased, whereas Cu, Fe, Zn, and Ca levels, CaE and GR activities, and GSH levels decreased compared with the control group. In the PbAc + N group, these alterations were markedly reversed, and structural kidney damage attributable to PbAc showed improvement. Additionally, PI3K and Akt1 immunoreactivity in kidney tissue was higher in the PbAc group than in the other groups. These findings indicate that PbAc induces oxidative stress, essential element imbalance, and histopathological damage via ROS-mediated activation of PI3K/Akt, while N mitigates these processes and significantly attenuates nephrotoxicity. N appears to be a promising therapeutic candidate against PbAc-induced kidney injury; however, further clinical studies are warranted for validation. Keywords: Lead acetate; Naringin; Nephrotoxicity; PI3K/AKT pathway