Abstract: FR-PO1186
Metabolic Landscape of Naturally Occurring CKD in Cats: An Integrated Multiomics Study
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Li, Qinghong, Nestle Purina PetCare Co, Saint Louis, Missouri, United States
- Cominetti, Ornella, Nestle Research, Lausanne, Swaziland
- Migliavacca, Eugenia, Nestle Research, Lausanne, Swaziland
- Holzwarth, James, Nestle Research, Lausanne, Swaziland
- Karaz, Sonia, Nestle Research, Lausanne, Swaziland
- Membrez, Mathieu, Nestle Research, Lausanne, Swaziland
- Macron, Charlotte, Nestle Research, Lausanne, Swaziland
- Courtet-Compondu, Marie-Claude, Nestle Research, Lausanne, Swaziland
- Summers, Stacie, Oregon State University, Corvallis, Oregon, United States
- Sorrentino, Vincenzo, National University of Singapore, Singapore, Singapore
- Dayon, Loïc, Nestle Research, Lausanne, Swaziland
Background
Human and feline CKD shares similar pathophysiology, including chronic tubulointerstitial inflammation and fibrosis. The underlying mechanisms for both diseases are incompletely understood. This study outlined our first step towards creating a metabolic atlas of feline CKD.
Methods
Cats diagnosed with CKD were staged according to the International Renal Interest Society guidelines. Targeted and untargeted metabolomics was performed on serum samples. Transcriptomics and proteomics were performed on cortical and medullar tissues from cats euthanized for humane reasons unrelated to the study. Linear model was applied for data analysis with false discovery rate (FDR)<0.05 for differential metabolites and genes, and FDR<0.15 for differential proteins between groups.
Results
Serum concentrations of free fatty acids, 3-hydroxy fatty acids, and acylcarnitines were elevated, while renal RNA and protein expressions of enzymes for fatty acid transport and oxidation were downregulated in CKD cats compared to control cats. Tissue protein expressions of several glycolytic enzymes were increased but decreased for gluconeogenic enzymes in CKD cats. While the levels of oxidized glutathione, glutamine and several Krebs cycle intermediates accumulated in the circulation, tissue RNA and protein expressions of enzymes involved in glutathione biosynthesis, glutaminolysis, Krebs cycle, ketolysis, and NAD+ biosynthesis were reduced in CKD cats compared to control cats. Further, tissue gene expressions of profibrotic (TGFβ1, CTGF, GAL3, α-SMA, FN1, LOX) and proinflammatory (IL11, IL16, TNF) markers, and hypoxia inducible factor HIF1A were upregulated, while gene expressions of anti-fibrotic klotho and hypoxia inhibitors (FIH1, PHD2) were downregulated in CKD cats vs control cats. Finally, targeted metabolomics revealed elevated circulating uremic toxins, including TMAO, indoxyl sulfate, p-cresol sulfate, phenol sulfate, while RNA expressions of renal tubular transporters OAT1, OATP4C1 and ABCC2 were downregulated in cats with CKD.
Conclusion
Our study unveiled extensive abnormalities and readaptations in bioenergetics, impaired redox homeostasis and uremic toxin excretion, and increased inflammation, fibrosis, and hypoxia in cats with CKD.
Funding
- Commercial Support – Nestle Purina PetCare Company