Temporal proteomic profiling of mouse kidney reveals dynamic responses to Crotalus durissus terrificus envenomation.

Snakebite envenoming by Crotalus durissus terrificus causes significant morbidity, particularly acute kidney injury (AKI), though its molecular mechanisms remain poorly understood. This study provides the first comprehensive temporal proteomic atlas of renal responses to C. d. terrificus envenomation, combining TMT-based quantitative proteomics with multivariate bioinformatics and histopathological validation in a mouse model (0.5 LD50). We identified 2567 renal proteins, with 904 significantly altered (FDR ≤ 0.05), demonstrating a proteomic crisis that peaked at 12 h (400 increased, 451 decreased) and was already evident at 6 h (15 increased, 37 decreased). Changes at 1 h and 24 h were minimal at the single-protein level. These results delineate a precise biphasic progression: from acute phase at 6 h to 12 h, characterized by oxidative stress, mitochondrial dysfunction, and loss of key tubular transport proteins dominated by maladaptive repair and fibrotic signaling. Our temporal analysis defines distinct windows for intervention: an early opportunity for antioxidant therapy to counter acute injury, followed by a critical period where anti-fibrotic strategies are required to prevent the progression to irreversible kidney damage. SIGNIFICANCE: Snakebite envenomation by Crotalus durissus terrificus rattlesnake venom frequently leads to acute kidney injury (AKI), yet the molecular mechanisms driving nephrotoxicity remain poorly characterized. This study provides the first comprehensive temporal proteomic atlas of renal responses to envenomation, revealing that the most robust proteomic remodeling occurs between 6 h and 12 h, with hundreds of proteins significantly altered. These changes highlight mitochondrial dysfunction, oxidative stress, and tubular injury, exemplified by decrease of CUBN and AGT, alongside shifts in cytoskeletal and ribosomal pathways. Early (1 h) and late (24 h) effects were limited at the single-protein level and are reported as exploratory trends, such as NDRG2 (hypoxia response) and ITGA3 (fibrotic signaling). Histological validation confirmed progressive tubular damage and maladaptive repair, paralleling the proteomic signatures. Together, these findings delineate a critical window of maximal molecular disruption at 12 h, providing mechanistic insights into the progression from acute injury to maladaptive remodeling. The data suggest that therapeutic strategies targeting early oxidative stress (e.g., antioxidant interventions) or late fibrotic pathways (e.g., RAS modulation) could mitigate venom-induced damage. This work bridges molecular pathophysiology with clinical outcomes, informing future translational research.