Interferon-? signaling in the progression from early to end stage kidney disease in type 2 diabetes
The effects of circulating pro-inflammatory factors on diabetic kidney disease (DKD) progression remain poorly defined. In this study, transcriptional and proteomic profiling of kidney tissue and blood samples from individuals with type 2 diabetes mellitus and early DKD was used to identify gene expression associated with kidney disease progression.  Interferon gamma (IFNG) was both identified as an upstream regulator of gene expression and detected in the serum of individuals who progressed.  Individual IFNG activation scores (representing summary expression of 72 downstream signaling mediators) early in disease correlated with DKD progression over an average of 9.7 years.  IFNG pathway inhibition reduced gene activity associated with DKD progression in both kidney organoids generated from human pluripotent stem cells and mouse DKD models.  Thus, expression of genes associated with IFNG activity early in DKD predicted disease progression; individuals demonstrating IFNG activity may benefit from targeted therapeutics early in the disease course. Overall design: Kidney organoids were generated from human embryonic stem cells (UM77-2, NIH registry #0278) according to published protocol (Harder et al., JCI Insight 2019).  Organoids were treated on day 23 with either vehicle control, or 25ng/ml of IFNg, or 1000nM of Baricitinib or the combination of IFNg with Baricitinib (added 1 hr prior to IFNg) for 24h. Then organoid whole wells were either RNA extracted for BulkRNA Seq processing or single cell dissociated for scRNASeq processing in the Advanced Genomics Core at the University of Michigan.