Tissue Inhibitor of Metalloproteinases-2 Mediates Kidney Injury during Sepsis

Introduction: Urinary tissue inhibitor of metalloproteinases (TIMP)-2 has been identified as a predictive marker for acute kidney injury (AKI), including sepsis-associated AKI (S-AKI). Whether TIMP-2 might be causally related to AKI and hence represent a viable drug target is unclear. Objective: The aim of this study was to evaluate whether suppression of TIMP-2 attenuates S-AKI. Methods: Balb/c mice were randomized to sham or cecal ligation and puncture surgery and treated with or without a TIMP-2-neutralizing antibody. Animals were followed for 48 h and then sacrificed for analysis of TIMP-2 expression, cell cycle, and histology. Results: Anti-TIMP-2 resulted in decreased lumen TIMP-2 expression which markedly increased cell cycle progression and attenuated epithelial cell injury by histology. Conclusions: TIMP-2 mediates S-AKI and appears to be a viable drug target.