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Abstract: PO0649

Interferon-γ Signaling and the Progression of Early Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 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
  • Looker, Helen C., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Brosius, Frank C., University of Arizona, Tucson, Arizona, United States
  • Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, 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

Inflammation plays an important role in pathogenesis of diabetic kidney disease (DKD). However, the pathways by which circulating pro-inflammatory factors activate intrarenal signaling and mediate DKD progression remain poorly defined. Using multiscalar data integration we aimed to identify links between circulating factors in early DKD and activation of kidney signaling pathways and DKD progression

Methods

Transcriptomic data from kidney biopsies of Pima Indians with type 2 diabetes and early DKD (n=74) were used to identify differentially expressed genes (DEGs) and their upstream regulators (URs) associated with end-stage kidney disease (ESKD). Plasma proteomics (n=162) was used to identify ESKD-associated circulating proteins. URs were selected if their regulation in plasma was consistent with the prediction based on transcriptomic analysis. Activation scores were computed based on the downstream signaling cascade at the transcriptomic level and then associated with structural lesions and health outcomes in DKD patients. The findings were validated in podocyte-specific JAK2 transgenic Ins2Akita/+ mice (Pod-Jak2TG-Akita) which develop progressive DKD and in human kidney organoid cultures.

Results

Five URs of ESKD-associated DEGs in both glomeruli (Glom) and tubulointerstitium (TI) were identified, with interferon gamma (IFNG) exhibiting the most significant association. IFNG receptor expression was detected in multiple kidney cell types by single cell RNAseq analysis. Higher IFNG pathway kidney activation scores in Glom and TI were associated with increased risk of ESKD and faster GFR decline over 10.5 years. Inhibition of the IFNG pathway reduced kidney IFNG score and ameliorated albuminuria and mesangial expansion in Pod-Jak2TG-Akita mice. IFNG significantly increased IFNG activation score in human organoids, which was reduced by baricitinib, an inhibitor of JAK1 and JAK2, which are major IFNG signaling mediators.

Conclusion

Increased circulating IFNG levels and IFNG pathway activation in kidney tissue in early DKD may lead to DKD progression. Therefore, the IFNG pathway may be a target for intervention in early DKD.

Funding

  • NIDDK Support