Kidney Week

Abstract: TH-OR076

SGLT2 Inhibitors Reverse Hypoxia-Inducible Factor (HIF)-1A Regulatory Network Activation in Diabetic Kidney Disease

Session Information

• Precision Medicine in Diabetic Kidney Disease: Biomarkers, Combination Therapies, and Treatment Response Prediction
  November 06, 2025 | Location: Room 372A, Convention Center
  Abstract Time: 05:00 PM - 05:10 PM

Category: Diabetic Kidney Disease

• 702 Diabetic Kidney Disease: Clinical

Authors

• Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States

Jennifer A. Schaub, MD

• Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States

Viji Nair, PhD

• Minakawa, Akihiro, University of Michigan, Ann Arbor, Michigan, United States

Akihiro Minakawa, MD, PhD

• Smith, Cathy, University of Michigan, Ann Arbor, Michigan, United States

Cathy Smith, PhD

• Berthier, Celine C., University of Michigan, Ann Arbor, Michigan, United States

Celine C. Berthier, PhD

• Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States

Rajasree Menon, PhD

• Nelson, Peter J., University of Michigan, Ann Arbor, Michigan, United States

Peter J. Nelson, PhD

• Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States

Jennifer L. Harder, MD, FASN

• Bjornstad, Petter, University of Washington, Seattle, Washington, United States

Petter Bjornstad, MD

• Werner, Thomas Bernd, University of Michigan, Ann Arbor, Michigan, United States

Thomas Bernd Werner, PhD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

Group or Team Name

• For the Kidney Precision Medicine Project (KPMP).

Background

Hypoxic stress contributes to damage in renal tubules associated with type 2 diabetes (T2D). SGLT2 inhibitors (SGLT2i) may help reduce hypoxia in T2D.

Methods

A HIF1A regulatory gene network was used to evaluate the potential therapeutic targeting of hypoxic damage by SGLT2i in T2D.

Results

HIF1A is a key transcription factor (TF) in hypoxia. Single-cell RNA sequencing (scRNAseq) from kidney biopsies of youth with T2D showed that 172 HIF1A regulated transcripts exhibited cell type enrichment, which validated in individuals with T2D from KPMP. Comparative promoter analysis of the 172 HIF1A-regulated genes identified conserved promoter structures linked to HIF1A, which coordinate the co-expression of genes. The 172 gene hypoxic network was expanded by using the resultant HIF1A containing structures (predominantly comprised of KLF and ETS family TFs) in genome wide searches to identify additional potential hypoxia-associated genes outside the original gene list yielding a reconstructed network of 237 genes consisting of 7 overlapping pathways linked to hypoxic stress. In multiome data from KPMP, 85% of the promoters in the network were in open accessible chromatin and 62 network genes had differentially accessible chromatin and differential expression between adaptive proximal tubular cells (PT) and healthy PT. Using RNAseq data from early (urine albumin/creatinine (uACR) >30 and <300 mg/g, eGFR<90 ml/min/1.73 m²) and late DKD (uACR>300 mg/g, eGFR<90ml/min/1.73 m²) progressive changes in the network were documented. The network was validated in hypoxic organoids. scRNAseq from PT cells of youth with T2D demonstrated that the perturbations seen in the network with disease were effectively rescued following SGLT2i treatment.

Conclusion

This study suggests that intervention with SGLT2i may reduce damage associated with hypoxic stress.

Youth with T2D treated with SGLT2i had HIF1A regulatory network closer to healthy control state (HC) compared to untreated T2D.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025hxmr242p