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Abstract: FR-PO351

Single Nucleus RNA Sequencing of Sglt2 Knockout Mouse Hearts Reveals Cardiac-Renal Communication

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Fain, Margaret E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Maekawa, Hiroshi, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Rousselle, Thomas, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Monroe, Tanner O., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Mas, Valeria R., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a class of drugs that promote glycosuria and have been shown to provide marked cardiac and renal benefit regardless of diabetes status; however, the precise mechanism of this benefit to the heart is unclear, especially given that the canonical target for SGLT2is is a cotransporter only expressed in the proximal tubule of the kidney. To investigate the broader cardiac effects of chronic Sglt2 inhibition, we conducted the first single-nucleus RNA sequencing (snRNA seq) experiment in the hearts of the SweetPee (SP) mouse model, which carries a missense mutation in the Slc5a2 gene resulting in loss of Sglt2 expression in the proximal tubule of the kidney.

Methods

10-week-old male SP and wildtype (WT) control littermates were fed either normal diet (ND) or high fat diet (HFD, 60% calories from fat) for 18 weeks. Hearts were processed using single-nucleus RNA sequencing (snRNA seq) and the resulting data were analyzed through the Seurat pipeline in R to identify differentially expressed genes (DEGs) and to perform pathway enrichment.

Results

Clustering revealed twenty different cell types, no one of which was significantly enriched in any of the four conditions. Replicating prior observations, Slc5a2 was not expressed in any cardiac cell type under any condition. In the WT HFD group, genes encoding molecules involved in oxidative phosphorylation were upregulated in cardiomyocytes, alongside other metabolic genes. These changes are consistent with altered mitochondrial function. By contrast, the SP HFD showed a downregulation in genes associated with diabetic cardiomyopathy and an upregulation of angiogenic genes. The changes in the WT HFD group are predicted to be deleterious, while those in SP HFD appear to be protective, supporting a model of organ crosstalk whereby renal Sglt2 inhibition results in protective molecular changes in cardiomyocytes.

Conclusion

Here, we demonstrate for the first time that loss of function of the proximal tubule-specific Sglt2 co-transporter results in significant upregulation of cardio-protective pathways, indicating that the cardiac benefit of SGLT2is is secondary to primary effects on the kidney and not a result of off-target pharmacologic effects.

Funding

  • NIDDK Support