Abstract: SA-PO0179
Inhibition of NLRP3 Signalling Improves Kidney Function in Preclinical Models of AKI
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Seth, Asha, AstraZeneca PLC, Cambridge, England, United Kingdom
- Veenit, Vandana, AstraZeneca PLC, Cambridge, England, United Kingdom
- Hovdal, Daniel, AstraZeneca PLC, Cambridge, England, United Kingdom
- Franzin, Rossana, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Staffieri, Francesco, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Crovace, Antonio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Charrin, Emmanuelle, AstraZeneca PLC, Cambridge, England, United Kingdom
- Pearce, Andy, AstraZeneca PLC, Cambridge, England, United Kingdom
- Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Woollard, Kevin, AstraZeneca PLC, Cambridge, England, United Kingdom
Background
Acute kidney injury (AKI) is a severe clinical condition that can develop due to a number of insults including sepsis, ischemia-reperfusion injury (IRI), nephrotoxicity, dehydration and urinary tract obstruction. The NLRP3 inflammasome is a multi-protein complex involved in the innate immune system response to infection and endogenous cellular damage. However excessive inflammasome activation is associated with AKI. AZD4144 is a novel small molecule inhibitor which binds to NLRP3 and prevents subsequent inflammasome activation and is in clinical development as a therapeutic approach for AKI treatment.
Methods
In vitro experiments assessed the effect of NLRP3 inhibition on ASC speck formation, downstream cytokine release in primary and immortalised macrophages and NETosis by primary neutrophils. In vivo, mice were treated with LPS to induce AKI and with AZD4144 or control vehicle. In addition, we developed a porcine model of bilateral IRI. In both models, renal function was evaluated via plasma creatinine and blood urea nitrogen (BUN), plasma IL-1β, IL-18 and urinary IL-18 levels were measured.
Results
Inhibition of NLRP3 by AZD4144 resulted in a reduction of speck formation and the release of IL-1β and IL-18 in macrophages stimulated with LPS and nigericin. AZD4144 effectively inhibited NETosis in-vitro. Furthermore, AZD4144 administration in-vivo decreased plasma IL-1β and IL-18 levels, as well as urinary IL-18, and conferred protection against renal dysfunction induced by LPS, as indicated by a significant dose-dependent reduction in plasma creatinine and BUN. Extracellular citrullinated H3, a biomarker for NETosis was also decreased by AZD4144 in the LPS model. To translate our fundings we developed a 7-day swine model of ischemic AKI, where we observed NLRP3 inhibitor treatment significantly improved kidney function.
Conclusion
AZD4144 reduces cytokine release and NETosis in vitro and in vivo. NLRP3 inhibition significantly reduces kidney injury in preclinical models of AKI. These findings support the therapeutic potential of AZD4144 for AKI.
Funding
- Commercial Support – Astrazeneca