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Abstract: FR-PO1077

The Oxidized Linoleic Acid Metabolite 12,13-Dihydroxy-9Z-Octadecanoid Acid (12,13-DiHOME) Mediates Recovery from Nephrotoxic Nephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Kvirkvelia, Nino, Augusta University, Augusta, Georgia, United States
  • McMenamin, Malgorzata, Augusta University, Augusta, Georgia, United States
  • Ibrahim, Ahmed, Augusta University, Augusta, United States
  • Al-Shabrawey, Mohamed, Augusta University, Augusta, Georgia, United States
  • Madaio, Michael P., Augusta University, Augusta, Georgia, United States
Background

The number of anti-inflammatory lipid molecules is increasing and their role in nephritis is not well investigated. In particular, the enzymatic activity of soluble Epoxide Hydrolyze (sHE) and its products such as 9,10-DiHOME and 12,13-DiHOME were shown to be critical for resolution of inflammation. Biosynthesis of these products starts from linoleic acid by cytochrome P450 (CYP) oxidases, followed by hydrolysis catalyzed by soluble epoxide hydrolases. We hypothesized that synthesis, metabolism or signaling of oxidized linoleic acid metabolites may be affected at the site of inflammation and that 12,13-DiHOME has an important role in resolution of nephritis.

Methods

To investigate changes in lipid profiles in differentially treated mice, lipidomic analysis was carried out by LC/MC in Lipidomics Core Facility (Wayne State University, Detroit, MI). Panel of 144 lipid molecules were measured in plasma of mice at day 7 after induction of nephrotoxic nephritis (NTN), induced by injection of nephrotoxic serum (13,5µl/g bw). Kidney endothelial cells were treated with 12,13-DiHOME (250nM) and TNF-α (10ng/ml) was added after 1h. TNF-α induced upregulation of VCAM-1 was investigated by flow cytometry after 24 h.

Results

Lipidomic plasma profiles of polyunsaturated fatty acid metabolites in nephrotic mice showed marked decrease of two molecules: 9,10-DiHOME and 12,13-DiHOME. The role of 12,13-DiHOME was further evaluated in NTN: after induction of nephritis mice were treated with 12,13-DiHOME (20ng/g bw) or vehicle, starting on day 2, than every 48h, and mice were sacrificed on day 7. 12,13-DiHOME treatment completely normalized both BUN levels and histology (NTN mice: BUN = 117.72 ± 3.2, NTN 12,13-DiHOME injected mice BUN = 15.50 ± 0.43, p<0.0002). In glomerular endothelial cells, 12,13-DiHOME treatment reduced TNF-α induced upregulation of VCAM-1 by 49%.

Conclusion

The results of the study suggest that administration of 12,13-DiHOME during NTN protects kidneys from severe inflammation, in part, by limiting upregulation of adhesion molecules on kidney endothelial cells and therefore, may have therapeutic potential for the treatment of nephritis.

Funding

  • NIDDK Support