Interferon-γ 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.