Acute Renal Injury Induced by Apis mellifera Venom: Histopathological and Proteomic Insights into the Mechanisms of Nephrotoxicity

Bee venom (BV) envenomation is an underrecognized public health concern in tropical regions, including Brazil, where reported cases have increased by 144% over the past decade. The absence of a specific treatment for severe envenomation highlights the need to clarify its mechanisms of toxicity. This study investigated the acute toxicity of Apis mellifera venom by estimating its LD₅₀ and examining time-dependent tissue lesions, particularly in the kidneys, alongside renal proteomic changes. Swiss mice of both sexes (25–35 g; CEUA-ID 000645) received BV subcutaneously (0, 3, 10, 30, 100 or 300 μg/g; n=4–8/group) for LD₅₀ determination, with mortality recorded for 48 h. In a time-course experiment, mice received the estimated LD₅₀ (7.6 μg/g) and were euthanized at 0.5, 4, 12, 24 or 48 h (n=3–5/group). Brain, heart, lungs, liver, kidneys and duodenum were collected for histopathology; lesions were graded on a four-point scale. Renal tissue was also subjected to proteomic analysis. Mortality increased with dose, reaching 67% at 10 μg/g and 100% at 300 μg/g, whereas no deaths occurred at 0–3 μg/g. Macroscopic hematuria was observed from 4 h. The kidneys showed the most prominent lesions: mild tubular necrosis was already present at 30 min, and mild tubular casts appeared from 4 h; both progressed to moderate severity by 48 h. Temporal proteomics revealed significant changes in proteins associated with actin and microtubule organization, focal adhesions and cytoskeleton–membrane interactions (including MYH11, TPM3, DST, DLG1, PARVA, TUBA1A/TUBA1C, EPB41L3 and NHERF2), suggesting disruption of podocyte and tubular cell architecture. Altered EIF2S1, HSPH1 and ST13 pointed to proteotoxic stress and translational regulation, while changes in mitochondrial and lipid-metabolism proteins (NDUFS5, MT-CYB, MTCO1, HMGCS2 and TECR) suggested impaired energy homeostasis. Differential abundance of LAMP1, AP3D1 and STXBP2, together with G-protein/Rho-signaling components, further implicated vesicular trafficking and cytoskeletal signaling. Overall, the findings indicate that A. mellifera venom induces rapid, progressive renal injury accompanied by cytoskeletal remodeling, cellular stress and metabolic disturbance. These pathways may contribute to acute kidney dysfunction and warrant investigation as targets for renoprotective strategies.