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Abstract: SA-OR15

Cell Type Specificity of Hypoxia Signaling in Early Diabetic Kidney Disease (DKD)

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Schaub, Jennifer A., University of Michigan Health System, Ann Arbor, Michigan, United States
  • Menon, Rajasree, University of Michigan Health System, Ann Arbor, Michigan, United States
  • Nair, Viji, University of Michigan Health System, Ann Arbor, Michigan, United States
  • Otto, Edgar A., University of Michigan Health System, Ann Arbor, Michigan, United States
  • Weinberg, Joel M., University of Michigan Health System, Ann Arbor, Michigan, United States
  • Looker, Helen C., National Institutes of Health, Bethesda, Maryland, United States
  • Nelson, Robert G., National Institutes of Health, Bethesda, Maryland, United States
  • Kretzler, Matthias, University of Michigan Health System, Ann Arbor, Michigan, United States
Background

Chronic hypoxia is considered a driver of kidney disease progression. Given the spatial heterogeneity of hypoxia, we evaluated the cell type specificity of Hypoxia Related Genes (HRG) in DKD along the nephron and the association of HRG with structural parameters.

Methods

Cell-specific expression and normalized gene signatures (Z scores) were calculated for 237 HRG in single cell RNA profiles of 44 kidney biopsies from American Indians with Type 2 Diabetes (T2D) and 7 healthy living donor kidneys (LD), and replicated in 49 independent micro-dissected biopsies of T2D with DKD (DN).

Results

Mean measured glomerular filtration rate was 159 ml/min (SD 54) in T2D and 147 ml/min (SD 45) in DN, and mean urine albumin/creatinine ratio was 304 mg/g (SD 1542) for T2D and 35 mg/g (SD 90) for DN. Average HgA1c was 9.2 for T2D and 9.3 for DN. HRG expression showed highly cell-type specific elements in both LD and T2D (Figure 1). HRG signature in stressed proximal epithelial cells (sPEC), unique to T2D, was dominated by apoptosis and glycolysis signals, while endothelial cells (EC) signatures expressed more genes involved in fibrosis in T2D compared to LD. In DN, Z score of the EC signature was associated with increased mesangial volume (R 0.33, p-value 0.02) and Z score of sPEC signature was associated with interstitial fibrosis (R 0.35, p-value 0.02), which are strong predictors of long-term outcomes in this cohort.

Conclusion

HRG expression varies by cell type in LD and DKD, suggesting transcriptional regulation changes of HRG in diabetes and DKD. Association of HRG signatures with morphometrics that are associated with progressive GFR loss implicate chronic hypoxia processes in early DKD.

Figure 1: Heatmap of HRG in T2D

Funding

  • NIDDK Support