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Abstract: FR-PO686

Role of Eicosanoids in Hyperfiltration-Mediated Injury: Insights from Human Participants and a Mouse Model

Session Information

  • Pediatric Nephrology - 1
    October 25, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1900 Pediatric Nephrology

Authors

  • Srivastava, Tarak, Children's Mercy Kansas City, Kansas City, Missouri, United States
  • Milne, Ginger L., Vanderbilt University, Nashville, Tennessee, United States
  • Sharma, Mukut, Kansas City VA Medical Center, Kansas City, Missouri, United States
Background

The mechanism of hyperfiltration-mediated kidney injury in children with a solitary functioning kidney (SFK) is not known. Changes in vasoactive metabolites including Prostaglandin E2 (PGE2) modulate glomerular hemodynamics. We demonstrated upregulation of the cyclooxygenase-2-PGE2-Prostanoid receptor EP2 (COX2-PGE2-EP2) pathway in unilateral nephrectomy (UNX) mouse model of hyperfiltration-mediated kidney injury and its attenuation using EP2 and EP4 agonists and antagonists. Following these results, we hypothesize altered urinary eicosanoid profile in children with SFK and altered expression of eicosanoid metabolizing enzymes and receptors in UNX mice.

Methods

Children with SFK (n=57, 37 boys) and healthy children with monosymptomatic enuresis (N=72, 49 boys) were included. Data on age, gender, height, weight, blood pressure (BP) and a urine sample were collected during the clinic visit. Urinary metabolites of various eicosanoids were measured using liquid chromatography-tandem mass spectrometry (Eicosanoid Core Laboratory, University of Nashville TN). The Wilcoxon test was used for non-parametric analysis of human data. sv129 mice (4 weeks old) were used for Sham or UNX surgery and observed for 6 months. Mouse kidney cortical tissue was used for transcriptomic and proteomic analysis at the University of Missouri Core Facilities, Columbia MO, followed by bioinformatic analysis.

Results

Healthy children and children with SFK did not differ significantly in age, Z-scores for height, weight, and BP. However, urinary PGE2 (p=0.013), TxB2 (p=0.024), 11,12-DHET (p=0.003), and 14,15-DHET (p=0.011) were elevated in children with SFK compared to healthy children. No significant differences were found for other eicosanoids.
Transcriptomic and proteomic analyses of mouse kidney tissue showed that the expression of proteins related to PGE2 and TxB2 metabolism and activity, as well as cytochrome P450 enzymes, were significantly altered in the UNX group. Expression of Cbr1, Ptgr2, Akr1c14, Cyp2d12, and Cyp2j5 showed changes at both the gene and protein expression level (p<0.05).

Conclusion

Present data from children with SFK and UNX mouse model corroborate previous findings and suggest the importance of eicosanoids and related enzymes and receptor proteins in hyperfiltration-mediated kidney injury in SFK.

Funding

  • NIDDK Support