Treatment with Wedelolactone reverses AKI caused by Bothrops jararacussu envenomation.

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Summary: Snakebite-induced acute kidney injury (sAKI) is a severe clinical complication associated with Bothrops envenomation, often leading to renal failure and chronic kidney disease (CKD). This study evaluates the nephroprotective effects of wedelolactone (WEL), a bioactive coumestan derived from Eclipta prostata (EP), in a preclinical model of sAKI. Wistar rats were intramuscularly administered 3.5 mg/kg Bothrops jararacussu (Bj) venom to induce sAKI, followed by treatment with WEL (2, 5, or 10 mg/kg) two hours post-envenomation. At 5 mg/Kg, WEL effectively mitigated renal dysfunction, preserving glomerular filtration rate (GFR), and reducing proteinuria. Histological analysis revealed preserved kidney cytoarchitecture and reduced collagen deposition. Biochemical studies showed that WEL decreased matrix metalloproteinase (MMP) activity and nitrite levels, key contributors to Bj-induced nephrotoxicity, while antioxidant mechanisms were implicated in its protective effects. WEL 2 or 5 mg/Kg did not block Bj-induced muscle damage demonstrating that its molecular mechanism involves the direct impact of the venom in the kidney. Importantly, WEL did not affect kidney function in normal rats. These findings highlight the translational potential of WEL as a complementary therapeutic agent for managing sAKI and reducing the long-term burden of snakebite-related kidney disease. Experimental protocol: According to Romanelli et al., 2021 Two hours after envenomation, both Ctrl and Bj groups were further subdivided into WEL-treated subgroups, receiving one of the three different WEL doses (IM; 2, 5 or 10 mg/Kg) in the posterior region of the left thigh. This created the following final groups: Ctrl, Ctrl+W2, Ctrl+W5, Ctrl+W10, Bj, Bj+W2, Bj+W5, and Bj+W10. Graphics and Tables: Fig 1 Measure of muscle injury: using a caliper to quantify the extent of the injury. Table 2 andTtable 3. Renal function analysis according to Romanelli et al., 2021. Fig 2: Na+ transporters activity, measured accordin to Pereira-Acácio et al., 2022 Fig 5, 6 and 7. Kidney histomorphometric parameters Fig 6. Matrix metalloproteinase activity according to Soeiro et al., 2021 Fig 9. ER Stresse markers by western blot analysis Fig 10. Oxidative stress, according to Bryan et al., 2007 and Figueiredo-Junior et al., 2022. Histological Images - Fig 5, 6 and 7 Western blot - Fig 2A and 9 Multiple group comparisons were performed using one-way analysis of variance (ANOVA) followed by Sidak's post hoc test. Statistical analysis were conducted to compare WEL treatment effects in healthy rats (Ctrl vs Ctrl+W2, Ctrl+W5 or Ctrl+W10 groups), the impact of Bj venom exposure (Ctrl vs Bj groups) and the effects of WEL treatment following Bj envenomation (Bj vs Bj+W2, Bj+W5 or Bj+W10 groups). A p value < 0.05 was considered statistically significant. Statistical tests and graphs generation were performed using GraphPad Prism 8.0.2 software (GraphPad Inc., La Jolla, CA).

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