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Abstract: FR-OR33

Interferon-γ (IFN-g) Signaling in Diabetic Kidney Disease (DKD) Associated with ESKD

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States
  • El Saghir, Jamal, University of Michigan, Ann Arbor, Michigan, United States
  • Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
  • Harlan, Shannon Marie, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Baker, Hana, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Brosius, Frank C., University of Arizona, Tucson, Arizona, United States
  • Duffin, Kevin L., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Nelson, Robert G., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
Background

The mechanisms by which circulating pro-inflammatory factors modulate kidney signaling and disease progression in DKD remain poorly defined.

Methods

SOMASCAN plasma proteomics (n=162) and RNA profiles (n=74) from kidney biopsies of Southwest Native Americans with type 2 diabetes were used to identify differentially expressed genes (DEGs) and proteins and upstream regulators (URs) associated with progression to ESKD. Based on quantitative transcriptomic analysis, activation scores for IFN-g signaling were computed and associated with structural lesions and outcomes in DKD patients. These findings were validated in cultured human kidney cell lines, kidney tissue from 2 DKD mouse models (DBA/2 podocyte-JAK2 transgenic and uninephrectomized BKS ReninAAV db/db mice) and human kidney organoid cultures.

Results

Plasma IFN-g was upregulated in ESKD patients and identified as the top predicted UR for ESKD-associated kidney DEGs. Higher IFN-g activation scores, in both glomeruli and tubulo-interstitium correlated (r=0.40 and 0.35, respectively, p<0.05) with faster GFR decline. Participants with higher scores were more likely to reach ESKD (p<0.05). IFN-g significantly increased activation scores in cultured human kidney podocytes and proximal tubular cells (p<0.0001). Inhibition of the IFN-g pathway by a JAK1/2 inhibitor baricitinib reduced the activation scores and ameliorated albuminuria and mesangial expansion in podocyte JAK2 transgenic DBA/2 mice. Similar phenotypic improvements were observed in ReninAAV db/db uNx mice after treatment with the JAK1/2 inhibitor, ruxolitinib. Single cell profiling of IFN-g-treated organoids demonstrated the presence of IFN-g receptors and downstream target gene CXCL10 in kidney cell types. Higher kidney organoid IFN-g scores following stimulation with IFNG were suppressed with baricitinib. Secreted CXCL10 protein strongly associated with the IFN-g activation score in organoids.

Conclusion

Circulating IFN-g levels were directly associated with alterations in kidney transcriptomic programs and the progression to ESKD in human DKD and multiple models. A clinically available drug (baricitinib) reversed IFN-g activation and albuminuria in murine models identifying IFN-g as a target for treatment in DKD.

Funding

  • NIDDK Support