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Kidney Week

Abstract: FR-PO364

Deciphering Renal Restoration: Single-Cell Transcriptional Insights from Pre- and Post-Vertical Sleeve Gastrectomy Kidney Biopsies

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
  • Alakwaa, Fadhl, University of Michigan, Ann Arbor, Michigan, United States
  • Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States
  • McCown, Phillip J., University of Michigan, Ann Arbor, Michigan, United States
  • Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
  • Ladd, Patricia E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Vigers, Tim, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Pyle, Laura, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Choi, Ye Ji, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Ryder, Justin R., Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Brosius, Frank C., Banner University Medical Center Tucson, Tucson, Arizona, United States
  • Nelson, Robert G., National Institutes of Health, Bethesda, Maryland, United States
  • Nadeau, Kristen, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Bjornstad, Petter, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background

Vertical sleeve gastrectomy (VSG) attenuates the metabolic dysfunction characteristic of obesity and type 2 diabetes. The molecular mechanisms diminishing risk of kidney disease by VSG remain unclear.

Methods

Cell-type-specific differentially expressed genes (DEGs) before and 12 months after VSG (n=5 pairs) were determined from single-cell RNA sequencing (scRNAseq) of kidney biopsies. Top up-and downregulated pathways associated with VSG based on pathway enrichment of DEGs were compared with similarly curated Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) effects (https://doi.org/10.1172/JCI164486) to identify shared and unique pathways in cell types experiencing significant transcriptional changes.

Results

VSG improved UACR for all, and 75% with initial high albuminuria saw a category stepdown. Glomerular and mesangial volume decreased in the subset with kidney biopsy data. Proximal tubular cells had the most genes suppressed, while thick ascending limb cells the most enhanced, after VSG based on scRNAseq. Metabolic pathways like glycolysis, the TCA cycle, and gluconeogenesis were downregulated, while others like RTK signaling and axon guidance were upregulated across the nephron. Noteworthy transcriptional variations were seen between SGLT2i treatment and VSG (Figure).

Conclusion

scRNAseq provided insights into cell-specific effects of VSG on kidneys. Despite commonalities, VSG and SGLT2i modified distinct cell-specific signaling pathways, offering potential avenues for innovative therapeutic interventions.

Funding

  • NIDDK Support