Abstract: SA-PO093
The Initiating Effect of Acute-Phase Serum Amyloid A (A-SAA) on AKI
Session Information
- AKI: Inflammation and Cell Cycle
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Dier, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Fu, Haiyan, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
Background
Acute kidney injury (AKI) is a common and rapidly progressing condition lacking effective therapies. Understanding key molecular events during AKI initiation and progression is crucial. This project aims to identify factors that trigger AKI. Integrating biological experiments, bioinformatics, and mathematical modeling, we identified acute-phase serum amyloid A (A-SAA) as a key initiating molecule.
Methods
We constructed ischemia/reperfusion injury (IRI)-induced AKI model in mice and analyzed renal tissue proteome changes at various post-surgery time points using mass spectrometry. Bioinformatics and mathematical modeling identified AKI initiating factors. A-SAA knockout mice were used to create IRI- or cisplatin-induced AKI models. We assessed kidney injury severity through histological, immunological, and molecular biology techniques. In vitro, hypoxia/reoxygenation-induced and cisplatin-induced models were used to study A-SAA’s mechanisms. Primary cells and cell lines were used to examine A-SAA’s function and tubule-macrophage interactions. A recombinant protein vaccine against A-SAA was designed and tested in mice for therapeutic potential. Additionally, serum A-SAA levels were measured in patients undergoing cardiac surgery to assess its predictive value for AKI.
Results
A-SAA levels surged in serum and kidney tissue within 4 hours post-IRI. Initially expressed in tubule epithelial cells, A-SAA later appeared in various kidney cells. Proteomic data analysis using the Hopfield model highlighted A-SAA as a critical AKI driver, significantly influencing other protein expressions. A-SAA knockout reduced IRI- or cisplatin-induced AKI in male mice, evidenced by decreased tubule cell injury and inflammation. Mechanistically, A-SAA bound to CD36 and TLR4, aggravating cell injury, apoptosis, and inflammatory response, creating a harmful inflammatory microenvironment. A-SAA also recruited and activated macrophages, further worsening the microenvironment. The A-SAA vaccine induced antibodies in mice and showed reno-protective effects against AKI. Serum A-SAA levels in cardiac surgery patients correlated with AKI severity.
Conclusion
A-SAA is a critical driver in early AKI stages. By binding CD36 and TLR4, A-SAA damages tubule cells and recruits activated macrophages, creating a detrimental inflammatory microenvironment that exacerbates AKI. Targeting A-SAA could mitigate kidney injury and serve as an early AKI warning signal.
Funding
- Government Support – Non-U.S.