Systemic toxicity of snake venom metalloproteinases: Multi-omics analyses of kidney and blood plasma disturbances in a mouse model

Author(s):Show less -

Trevisan-Silva, Dilza ; Cosenza-Contreras, Miguel ; Oliveira, Ursula C. ; Da Ros, Nancy ; Andrade-Silva, Debora ; Menezes, Milene C. ; Oliveira, Ana Karina ; Rosa, Jaqueline G. ; Sachetto, Ana T. A. ; Biniossek, Martin L. ; Pinter, Niko ; Santoro, Marcelo L. ; Nishiyama Jr, Milton Y. ; Schilling, Oliver ; Serrano, Solange M. T.

• Document type: Journal article
• Source: International Journal of Biological Macromolecules; v. 253, p. 17-pg., 2023-10-24.

Abstract

Snakebite envenomation is classified as a Neglected Tropical Disease. Bothrops jararaca venom induces kidney injury and coagulopathy. HF3, a hemorrhagic metalloproteinase of B. jararaca venom, participates in the envenomation pathogenesis. We evaluated the effects of HF3 in mouse kidney and blood plasma after injection in the thigh muscle, mimicking a snakebite. Transcriptomic analysis showed differential expression of 31 and 137 genes related to kidney pathology after 2 h and 6 h, respectively. However, only subtle changes were observed in kidney proteome, with differential abundance of 15 proteins after 6 h, including kidney injury markers. N-ter-minomic analysis of kidney proteins showed 420 proteinase-generated peptides compatible with meprin speci-ficity, indicating activation of host proteinases. Plasma analysis revealed differential abundance of 90 and 219 proteins, respectively, after 2 h and 6 h, including coagulation-cascade and complement-system components, and creatine-kinase, whereas a semi-specific search of N-terminal peptides indicated activation of endogenous proteinases. HF3 promoted host reactions, altering the gene expression and the proteolytic profile of kidney tissue, and inducing plasma proteome imbalance driven by changes in abundance and proteolysis. The overall response of the mouse underscores the systemic action of a hemorrhagic toxin that transcends local tissue damage and is related to known venom-induced systemic effects. (AU)

• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/23871-8 - Molecular characterization of the in vivo effects of the hemorrhagic metalloproteinase HF3: insights from the proteomic analysis of mouse plasma and kidney tissue
• Grantee: Dilza Trevisan Silva
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/13548-4 - Proteomic/Glycoproteomic characterization of the venoms of the Bothrops jararaca complex with emphasis on the N-terminome and N-glycome of toxins
• Grantee: Solange Maria de Toledo Serrano
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/00715-0 - Proteolytic enzymes from snake venoms trigger cascades of yet unknown molecular events
• Grantee: Dilza Trevisan Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral