Integrated multi-omics analysis of renal metabolism in domestic cats with spontaneous chronic kidney disease.

Chronic kidney disease (CKD) is the leading cause of mortality in aged cats. After injury, feline kidneys undergo extensive metabolic reprogramming, but a comprehensive evaluation is lacking. Here we show a multi-omics study including serum metabolomics from 14 healthy control, 15 early stages, 6 late stages CKD cats, and renal cortical and medullary tissue RNA sequencing and proteomics. The analysis reveals a spatiotemporal pattern of gene and protein expression changes. In the early stages, there are 6 differentially expressed genes in the cortex, while nearly 2000 in the medulla. The number in the cortex increases to more than 4000 in late stages. The study provides evidence of deranged bioenergetics in CKD: circulating fatty acids and acylcarnitines accumulate, while genes and proteins involved in fatty acid transport and oxidation are downregulated. Glucose and pyruvate metabolism is altered. Impaired glutamine metabolism contributes to both energy deficiency and acid-base imbalance. Additionally, there is a downregulation of redox enzymes, and overexpression of proinflammatory mediators in CKD. Gene expression of TGFβ1 is strongly and positively correlated with that of other fibrogenic genes. Finally, oxygen homeostasis is disrupted. Hypoxia signaling is upregulated, while expression of SGLT2 gene and protein is downregulated in cats with CKD. The data unveil profound metabolic abnormalities and adaptations in feline CKD.