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Kidney Week

Abstract: SA-PO152

Exposure to Systemic Hypoxia After Renal Ischemia Reperfusion Injury (IRI) Promotes Kidney Repair

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • O'Sullivan, James, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tiwari, Ratnakar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Borkowski, Gabriella, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kapitsinou, Pinelopi P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

We and others have shown that activation of hypoxic signaling prior to renal ischemia reperfusion injury (IRI) exerts renoprotective effects. However, it is unclear whether induction of hypoxia (Hx) after injury regulates kidney recovery. Here, we investigated how exposure to systemic hypoxia regulates post-IRI kidney repair.

Methods

Male C57/BL6 mice were subjected to uIRI via clamping for 25 minutes. 6-hrs post-injury, groups were placed in hypoxia chamber at 8% O2 for 24 or 72 hrs, while control groups remained in normoxia (Nx). Mice were then sacrificed and kidneys collected for bulk RNA-Seq, metabolomic analysis and histology, while serum was collected for metabolomic analysis.

Results

After exposure to 72 hrs of Hx or Nx following IRI, the Hx group was found to have significantly lower injury via kidney injury scoring on H&E stained tissue sections (3.3±0.5 Nx vs 2.2±0.4 Hx, P=0.02, n=4 Nx, n=4 Hx) and Kim1 gene expression (2.5 fold suppression compared to Nx, P=0.0002, n=4 Nx, n=4 Hx). Hypoxia exposure for 24 hours did not significantly reduce kidney injury scores, but did reduce Kim1 expression (P=0.03). KEGG/GO pathway analysis of RNA-Seq data at 72 hours revealed a prominent inflammatory signature in the downregulated genes, such as cytokine-cytokine receptor interaction, TNF and NF-κB pathways (KEGG), as well as immune response, inflammation response and cytokine production (GO), indicating hypoxia exposure attenuated post-ischemic renal inflammation. On the other hand, pathway analysis of upregulated genes showed significant enrichment for metabolic pathways such as tryptophan metabolism, PPAR signaling, glutathione metabolism, fatty acid degradation and retinol metabolism. Furthermore, quantitative assessment of kidney and serum metabolite profile using a comprehensive LC-MS metabolite panel, as well as a targeted LC-MS assay for tryptophan related metabolites were carried out. Here, we found significant increases in tryptophan pathway metabolites in kidney tissue and serum, such as kynurenine, xanthurenic acid, 3-hydroxy-anthranilic acid and NAD+.

Conclusion

In summary, exposure to hypoxia in the context of established ischemic injury promotes early reparative processes. Among the altered metabolic pathways, changes in tryptophan metabolism may contribute to the mechanisms by which hypoxia promotes adaptive repair.

Funding

  • NIDDK Support