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Abstract: PO0274

Renal Cytosolic Phospholipase A2 Mediates AKI in Humans

Session Information

Category: Acute Kidney Injury

  • 102 AKI: Clinical, Outcomes, and Trials

Authors

  • Asowata, Evans Ohenhen, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Krause, Fynn Niclas, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
  • Romoli, Simone, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Ling, Stephanie, Clinical Pharmacology & Safety Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Tan, Jennifer Y., Clinical Pharmacology & Safety Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Musial, Barbara, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Huang, Margaret M., Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
  • Mahbubani, Krishnaa T., Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
  • Griffin, Julian L., Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
  • Laerkegaard Hansen, Pernille B., Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • Saeb-Parsy, Kourosh, Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
  • Woollard, Kevin, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Background

Increasing evidence suggests that cytosolic phospholipase A2 (cPLA2) and prostaglandin E2 (PGE2) drive the progression of various forms of kidney disease. Whether renal cPLA2-dependent PGE2 production significantly contributes to the progression of acute kidney injury (AKI) in humans is currently unknown. We compared the lipidomic and metabolomic profile of kidneys from deceased transplant organ donors with or without AKI and used molecular and tissue culture techniques to investigate the role of cPLA2-PGE2 pathway in AKI.

Methods

Kidneys with or without AKI were collected from deceased human transplant organ donors (non AKI: 10 kidneys from 7 donors and AKI: 12 kidneys from 8 donors). We used LC-MS and mass-spectrometry imaging (MSI) to investigate the abundance of relevant metabolites, RT-PCR and Western blotting were used to examine the levels of lipid enzymes and PGE2 levels were investigated by ELISA. To determine whether cPLA2-PGE2 pathway mediates AKI, we stimulated RPTEC and human kidney organ culture using interleukin-1β (IL-1β) and cPLA2 inhibitor and investigated changes in kidney injury markers.

Results

To validate this human model of AKI, kidney injury (KIM-1 and NGAL) and inflammatory (IL-1β and IL-6) markers were significantly higher in kidneys collected from donors with AKI compared to kidneys collected from donors without AKI. Lipidomics showed significantly lower levels of phosphatidylcholine (PC) species (PC 29:1, 31:1, 32:4 and 35:5) and MSI showed significantly higher abundance of arachidonic acid and prostaglandins in kidneys from donors with AKI. Kidneys from donors with AKI demonstrated significant upregulation of cPLA2 mRNA and protein, and higher levels of PGE2, compared to kidneys without AKI. cPLA2 inhibitor significantly reduced PGE2 and kidney injury markers in IL-1β-stimulated RPTEC and human kidney organ culture model.

Conclusion

Lipidomics, MSI and molecular data identify changes in the PC-cPLA2-PGE2 pathway in human kidneys obtained from AKI donors. The inhibition of cPLA2 ameliorates kidney injury in vitro suggesting that this enzyme is a key driver of AKI in humans.

Funding

  • Commercial Support – Astrazeneca UK Ltd