Annexin A2 interferes with complement regulation within the glomerulus

The alternative pathway of complement is an important pathogenic driver of a variety of glomerular diseases. Factor H is a soluble complement regulatory protein, and it is known to play a critical role in protecting the kidney from alternative pathway-mediated injury. Other proteins, however, can interfere with complement regulation by Factor H, thereby predisposing the kidney to injury. Annexin A2 was previously shown to bind to Factor H and is expressed by several resident cell types in the kidney. In the current study, we show that extracellular annexin A2 binds to the region of Factor H encompassing short consensus repeats 6 to 8, impairing the ability of Factor H to regulate complement activation on the surface of glomerular endothelial cells and podocytes in vitro and in vivo. Annexin A2 does not, however, impair Factor H function on extracellular matrix or guinea pig erythrocytes. Targeted deletion of annexin A2 in mice attenuates cyclosporine-induced kidney injury in mice and deficiency of annexin A2 expression reduces complement activation on the surface of extracellular vesicles released from endothelial cells in this model. Review of publicly available kidney transcription datasets revealed that annexin A2 is expressed by several cell types in the kidney, and that expression is increased in multiple different disease states. Annexin A2, therefore, may serve as an intrinsic "positive regulator" of complement activation in the kidney, promoting the inflammatory response after various kidney insults.