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Abstract: TH-PO211

SGLT2 Inhibitors Enhance Metallothionein Expression in Kidney Proximal Tubules of Adolescents With Type 2 Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Alakwaa, Fadhl, University of Michigan, Ann Arbor, Michigan, United States
  • McCown, Phillip J., University of Michigan, Ann Arbor, Michigan, United States
  • Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
  • Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States
  • Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
  • Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Pyle, Laura, University of Colorado School of Medicine, Aurora, Colorado, United States
  • Harned, Roger K., University of Colorado School of Medicine, Aurora, Colorado, United States
  • Ladd, Patricia E., University of Colorado School of Medicine, Aurora, Colorado, United States
  • Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
  • Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
  • Nelson, Robert G., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Brosius, Frank C., University of Arizona, Tucson, Arizona, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Bjornstad, Petter, University of Colorado School of Medicine, Aurora, Colorado, United States

Group or Team Name

  • Kidney Precision Medicine Project
Background

Oxidative stress is a main contributor to diabetic kidney disease (DKD), and SGLT2 inhibitors (SGLT2i) mitigate DKD onset in type 2 diabetes (T2D). An investigation of cell-type specific molecular reprogramming in the kidney with SGLT2i treatment was undertaken in young persons with T2D.

Methods

Single-cell RNA sequencing (scRNAseq) profiles of young persons (17±2 years) with T2D, treated with SGLT2i (N=10, T2Di+) or not (N=6, T2Di-), and healthy controls (N=6, HC) were obtained from protocol kidney biopsies. Similarly derived scRNAseq data were available for living donors (N=20, LD), T2D Pima Indians with DKD (N=42), and Kidney Precision Medicine Project (N=12) cohorts. Analysis of scRNAseq data identified differentially expressed genes (DEGs). enrichR enabled pathway enrichment analysis of DEGs.

Results

All participants had normal to elevated GFR by iohexol clearance (185-224 ml/min). Similar occurrence of microalbuminuria (~20%) but lower HbA1c (6.1% vs. 7.3%) were observed in T2Di- compared to T2Di+ at screening. In the proximal tubular (PT) cluster (10,032 cells), 1003 genes elevated in T2Di- vs. HC were suppressed by SGLT2i (T2Di+ vs. T2Di-) while 176 repressed transcripts in T2Di+ were recovered with SGLT2i. Most metabolic pathways increased in T2Di- were suppressed in PT by SGLT2i, except metallothionein and insulin receptor signaling pathways, which were enhanced with SGLT2i exposure (p<0.05). Repression of metallothioneins in PT could be validated in two independent DKD cohorts (Fig.1).

Conclusion

SGLT2i treatment may rescue metallothionein expression in PT, consistent with a more favorable redox state.

Funding

  • NIDDK Support