Abstract: FR-PO091
P2X4 Receptor Deficiency Protects Against Ischemic AKI in Mice
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Han, Sang Jun, Columbia University College of Physicians and Surgeons, New York, New York, United States
- Kim, Mihwa, Columbia University College of Physicians and Surgeons, New York, New York, United States
- D'Agati, Vivette D., Columbia University College of Physicians and Surgeons, New York, New York, United States
- Lee, H. Thomas, Columbia University College of Physicians and Surgeons, New York, New York, United States
Background
Ischemic acute kidney injury (AKI) is a major clinical problem with high mortality and morbidity. Although P2X4 receptor induces inflammation and cell death in some cell types, the role for P2X4R in ischemic AKI is unknown. Here, we tested the hypothesis that P2X4R activation by ATP released from necrotic renal cells exacerbates ischemic AKI by promoting renal tubular epithelial inflammation and apoptosis.
Methods
Wild type or P2X4R knockout mice were subjected to sham surgery or 30 min kidney ischemia reperfusion (IR) injury. Twenty-four hours later, plasma and kidney were harvested to measure markers of kidney injury (plasma creatinine, blood urea nitrogen, kidney NGAL expression, necrosis scores), inflammation (neutrophil infiltration, pro-inflammatory cytokine/chemokine mRNA induction) and apoptosis (TUNEL staining).
Results
P2X4R knockout mice were protected against renal IR injury with decreased plasma creatinine (1.33 ± 0.17 mg/dL), blood urea nitrogen (91.4 ± 8.6 mg/dL), and NGAL mRNA (395.3 ± 74.4 fold increase over sham) compared to wild type mice (PCr = 2.36 ± 0.1 mg/dL, BUN = 115.1 ± 4.1 mg/dL, and NGAL mRNA = 1194.2 ± 169.2 fold increase over sham, N=4 for all groups). In addition, P2X4R knockout mice had lower necrotic (Jablonski Score reduction of 31 ± 5.6%, N=4) and apoptotic (reduced TUNEL positive cells by 78.2 ± 1.5%, N=4) tubular cells compared to wild type mice. P2X4R knockout mice were also protected against renal inflammation with lower pro-inflammatory cytokine/chemokine mRNA induction after renal IR (monocyte chemoattractant protein-1 [MCP-1] = 2.2 ± 0.7, macrophage inflammatory protein [MIP-2] = 34.1 ± 6, Interleukin 6 [IL-6] = 19.3 ± 0.1, and intercellular adhesion molecule 1 [ICAM-1] = 0.98 ± 0.2 fold increase over sham) compared to wild type mice (MCP-1 = 11.1 ± 1.7, MIP-2 = 206 ± 65.2, IL-6 = 123.5 ± 29.6 and ICAM-1 = 3.7 ± 0.4 fold increase over sham) after renal IR injury. Consistent with this, kidney neutrophil infiltration was reduced by 49.3 ± 5.7% (N=4) in P2X4R knockout mice compared to wild type mice after renal IR injury.
Conclusion
Taken together, our studies suggest that P2X4R activation exacerbates ischemic AKI by promoting renal tubular inflammation and apoptosis after renal IR injury. Our studies provide a novel insight into the pathophysiology of P2X4R in ischemic AKI, suggesting a potential therapy for ischemic AKI.
Funding
- Other NIH Support