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Abstract: FR-OR36

Multi-Omics Integration Links Angiopoietin-Tie Signaling Pathway Activation With Diabetic Kidney Disease Progression

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Nair, Viji, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Liu, Jiahao, Central South University, Changsha, Hunan, China
  • Zhao, Yiyang, Peking University First Hospital, Beijing, Beijing, China
  • Chang, Dongyuan, Peking University First Hospital, Beijing, Beijing, China
  • Limonte, Christine P., University of Washington, Seattle, Washington, United States
  • Bansal, Nisha, University of Washington, Seattle, Washington, United States
  • de Boer, Ian H., University of Washington, Seattle, Washington, United States
  • Chen, Min, Peking University First Hospital, Beijing, Beijing, China
  • Bitzer, Markus, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Group or Team Name

  • KPMP
Background

Identification of prognostic biomarkers and pathways reflective of underlying molecular mechanisms are critical for effective management of diabetes and chronic kidney disease. Our study aims to establish this link by integrating circulating biomarker and kidney transcriptomic profiles with disease progression

Methods

A marker panel of circulating proteins measured in SOMASCAN platform predicting composite outcome of ESRD or 40% baseline GFR reduction from the C-PROBE cohort was identified using a machine learning method. Validations were performed in Cardiovascular Health Study, CHS (N=3183) and a Chinese Cohort Study of Chronic Kidney Disease participants with DKD (N=210). An Angiopoietin/Tie (ANG-TIE) pathway score was generated using expression of ANG-TIE signaling mediators using transcriptomic data. Cell specific regulation of the pathway and receptors were evaluated using single cell RNAseq profiles of DKD participants from the Kidney Precision Medicine Project.

Results

The three-plasma marker panel (ANGPT2, CLEC4M, EGFR) significantly improved prediction of composite outcome in discovery (N=58) and validation group (N=68) over the clinical parameters, LR test p=0.003 and 0.0004, respectively. Plasma ANGPT2 remained significant in CHS (HR=1.50, 1.18:1.92) and Chinese cohort (HR=2.07, 1.39:3.09) with higher levels associated with increased risk of progression after adjusting for confounding factors including age, gender, race, diabeteic history, GFR, and ACR. The glomerular ANG-TIE pathway activation scores were elevated in progressors/advanced DKD in C-PROBE (p=0.02) and in an external cohort (p<0.01). This was further supported by higher Tyrosine-Protein Kinase Receptor TEK level in glomeruli and higher ANG-TIE activation scores in endothelial cells in DKD by ScRNASeq data. ANG-TIE pathway activation also showed positive correlation with plasma ANGPT2 levels (r=0.43, P=0.01).

Conclusion

Our work suggests that activation of ANG-TIE signaling in the kidneys underlies the association of plasma ANGPT2 with disease progression, thereby providing potential targets to prevent DKD progression.

Funding

  • NIDDK Support