Abstract 4140279: Myeloid/Macrophage Annexin A2 Promotes Kidney Fibrosis

Background: Annexin A2 is a Ca 2+ - and phospholipid-binding protein widely expressed in various cells and tissues. It acts as a cell surface receptor for tissue plasminogen activator (tPA) and plasminogen, regulating the homeostasis of blood coagulation, fibrinolysis and matrix degradation. However, its role in kidney fibrosis remains largely unknown. Our previous in vitro work has shown that annexin A2 mediates NF-κB activation and promotes macrophage M2 to M1 phenotypic change, suggesting a critical role of macrophage annexin A2 in kidney fibrogenesis. Methods: We generated a novel myeloid/macrophage-specific annexin A2 knockout mouse by crossbreeding LysMCre mice and annexin A2 flox mice. Unilateral ureteral obstruction (UUO) was induced in the myeloid/macrophage-specific annexin A2 knockout mice and their wildtype counterparts, as well as C57BL/6 mice. Renal histology was evaluated. Kidney fibrosis and renal annexin A2 level were examined in these mice. Results: After UUO injury, annexin A2 was dramatically induced in the fibrotic kidneys from C57BL/6 mice in a time-dependent manner, and its induction correlated with the extent of fibrotic injury as indicated by fibronectin deposition. Intriguingly, double immune staining analysis found that annexin A2 was dramatically induced in the interstitial F4/80-positive macrophages. It was further found that, after obstructive injury, myeloid/macrophage-specific annexin A2 knockout mice displayed significantly reduced tubular epithelial damage and dramatically decreased deposition of matrix components such as collagen and fibronectin than that of their control littermates. Additionally, obstruction-induced epithelial transdifferentiation was significantly reduced in the myeloid/macrophage specific-annexin A2 knockout mice as indicated by increase of Ecadherin and decrease of de novo induction of αSMA. Conclusion: Thus, it is clear that myeloid/macrophage annexin A2 promotes epithelial transdifferentiation and kidney fibrosis after obstructive injury.