Characterizing the Transcriptional Features that Underlie Established Injury and Disease Progression in Diabetic Kidney Disease.

BACKGROUND: Diabetes is the leading cause of kidney failure in the developed world. Despite its importance, the molecular events driving the pathogenesis of diabetic kidney disease (DKD) remain incompletely understood. We thus sought to employ transcriptional profiling of kidney biopsy tissue to uncover relationships between transcriptional features and clinical parameters related to established kidney injury and disease progression. METHODS: Using bulk RNA-seq, we comprehensively explored the human diabetic kidney transcriptome in the largest cohort of patients with DKD to be transcriptionally profiled to date. These data were combined with clinical indices of established injury (estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio, interstitial fibrosis, and glomerulosclerosis) and disease progression (rate of eGFR decline and progression to end-stage kidney disease), and integrated with previously published mouse and human datasets to better delineate the transcriptional features that characterize this disease. RESULTS: We profiled 50 diabetic kidney and 13 healthy control biopsies, identifying a global transcriptional signature of human diabetic kidney disease, which included nearly universal upregulation of NNMT and CD209, and downregulation of DUSP1. We next correlated the diabetic kidney transcriptome with parameters associated with established DKD injury, which we used to derive a molecular index of disease stage in DKD. Finally, using both the rate of eGFR decline and documented progression to kidney failure, we observed a novel association between slower progression of kidney disease and expression of genes related to intercalated cell functional identity, such as FOXI1 and subunits of the V-ATPase proton pump. CONCLUSIONS: In addition to shedding light on the molecular events underpinning its pathogenesis, our data will serve as a valuable resource to help accelerate the discovery of improved diagnostics and therapeutics for DKD.