Ontogenetic Shift in a Snake Venom Proteome Drives Distinct Proteomic Responses in Mouse Renal Mesangial Cells

Abstract Bothrops snakes are endemic to Latin America and are responsible for most medically relevant snakebites within the region. Bothrops jararaca venom proteome shows clear rearrangement upon neonate to adult transition. Similarly, the pharmacological activities displayed by the venom undergo a significant ontogenetic shift. This study evaluated the ontogenetic shifts in B. jararaca venom toxicity using SV40-MES13 cells to model murine glomerular nephrotoxicity. Cell viability assays revealed that adult venom possesses higher cytotoxic potency than newborn venom, reducing survival by over 30% at 4.0 μg/mL within 2 h, compared to just 15% for newborn venom. Label-free proteomics of cellular content and secretome across a concentration gradient demonstrated distinct, dose-dependent pathological mechanisms. At lower concentrations, adult venom induced a silent phase of molecular damage where cells remained viable but primed for apoptosis. Elevated concentrations of adult venom drove a pro-fibrotic phenotypic transition and extensive breakdown of extracellular matrix and cytoskeletal components, likely triggering detachment-induced anoikis. Conversely, newborn venom elicited a modest stress response. In the secretome, adult venom promoted extensive matrix degradation, whereas newborn venom increased adhesion proteins, and both venoms suggested activation of endogenous host proteases. This multicompartment approach provided a valuable framework for deciphering complex envenomation-induced tissue injury.