Serum Amyloid A1 Damages the Peritubular Capillary Network and Promotes Kidney Fibrosis

Background: The deterioration of the peritubular capillary network causes renal tissue ischemia and hypoxia, accelerating chronic kidney disease (CKD). Finding ways to mitigate endothelial cell injury and restore capillary density has been a persistent challenge. This project examines the pathological role and molecular mechanisms of serum amyloid A1 (SAA1), identified by our team as a kidney injury-associated molecule. Using multi-omics analysis and traditional biological experiments, we study SAA1 in CKD patients, mouse models, and in vitro endothelial cell injury models. Our goal is to deepen understanding of CKD pathogenesis, identify therapeutic targets, and develop effective prevention and treatment strategies. Methods: Proteomic analysis of renal tissue post-ischemia/reperfusion injury (IRI) in mice identified molecules driving renal fibrosis, validated in CKD mouse models and patient biopsy specimens. Gene knockout mice were used in CKD models induced by IRI or unilateral ureteral obstruction (UUO). We employed histology, pathology, immunology, biochemistry, and molecular biology to study expression characteristics and damage effects. In vitro, transcriptome sequencing and traditional experiments elucidated molecular mechanisms in an endothelial cell injury model. Results: Proteomic analysis of renal tissue post-ischemia/reperfusion injury (IRI) in mice identified molecules driving renal fibrosis, validated in CKD mouse models and patient biopsy specimens. Gene knockout mice were used in CKD models induced by IRI or unilateral ureteral obstruction (UUO). We employed histology, pathology, immunology, biochemistry, and molecular biology to study expression characteristics and damage effects. In vitro, transcriptome sequencing and traditional experiments elucidated molecular mechanisms in an endothelial cell injury model. Conclusion: SAA1 is critical in renal fibrosis development, causing endothelial cell damage, increasing vascular permeability, disrupting capillary integrity, exacerbating renal ischemia and hypoxia, and accelerating fibrosis via the CD36/JNK pathway. Targeting SAA1 significantly improves renal microcirculation and delays CKD progression. SAA1 vaccination shows promise as an innovative CKD therapy. Funding: Government Support – Non-U.S.