Renal Single-Nucleus Transcriptomic of a New Model of Cardiovascular-Kidney-Metabolic (CKM) Syndrome in Aging Swine

CKM syndrome entails pathophysiological interactions among the heart, the kidneys, and metabolic derangements. The specific cell populations implicated in renal injury have yet to be identified. We leveraged a new model of CKM syndrome in aging swine and single-nucleus RNA sequencing (snRNA-seq) to investigate the renal cell-specific transcriptomic profile and set the stage for future testing of potential new targets. Aging pigs with CKM syndrome were studied for 14 weeks. Kidneys were harvested, nuclei isolated, snRNA-seq performed, and UMAP plots generated using default parameters. Expression profiles of marker genes were visualized to define renal cell types, ranked by the number of differentially expressed genes (DEGs), and factored by the total number of cells per cell type. Top DEGs/cell type were visualized and their protein expression assessed in confirmatory studies. A total of 52,367 nuclei were analyzed. Thirty clusters were identified and filtered by canonical gene markers, revealing 20 renal cell types. Subsequent analysis of CKM syndrome kidneys showed that proximal tubular (PT) and immune (IM) cell subpopulations at 49.1% and 45.8% cells with DEGs, respectively, which were mainly implicated in microtubule organization and age-related inflammation (IL2-STAT5 signaling). Protein expression of 2-tubulin was downregulated in PT cells, whereas expression of STAT5 was upregulated in IM cells. The renal snRNA-seq transcriptomic landscape of a translational swine model of CKM syndrome identified PT and IM cells with the largest numbers of DEGs. Our observations may guide future studies aimed at modulating specific age-related renal abnormalities in CKM syndrome to slow disease progression.