AKI frequently leads to acute cardiac dysfunction, particularly cardiorenal syndrome type 3 (CRS-3), which is characterized by cardiac inflammation, mitochondrial impairment, and progressive fibrosis. Despite its prevalence and significant impact on patient outcomes, the precise molecular mechanisms underlying this AKI-induced cardiac damage and maladaptive remodeling remain poorly understood. There is a significant gap in knowledge in these specific pathways that disrupt the delicate balance between extracellular matrix (ECM) deposition and degradation, which is essential for proper cardiac function, which in turn results in impaired remodeling and overall cardiac dysfunction observed in CRS-3.
Our researchers have discovered a novel mechanism linking AKI to cardiac dysfunction by which AKI upregulates the serine protease inhibitor SerpinA3N in the heart. This upregulation directly inhibits Granzyme B (GZMB) activity, a serine protease crucial for extracellular matrix (ECM) degradation; this disrupts ECM homeostasis and promotes maladaptive cardiac fibrosis and impaired remodeling. The discovery of the SerpinA3N-GZMB axis as a driver of AKI-induced cardiac fibrosis is a novel pathway and a new therapeutic target for CRS-3.
SerpinA3N protein expression was significantly upregulated in the heart for AKI tissues compared to the control group as identified by LC-MS.