Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease

Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney -derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed X200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney tran-scriptome. T1D DKD groups showed 13 upregulated genes prevalently ex-pressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional stress scorethat reflected long-term decline of kidney function and could even identify nor-moalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.

Automated summary

By genome-wide sequencing of 200 urinary extracellular vesicle (uEV) mRNA samples from clinical studies, we identified potential candidate biomarkers and mechanisms for studying diabetic kidney disease (DKD) in Type 1 diabetes (T1D), which were validated in both Type 1 and 2 diabetes. The sequencing results revealed over 10,000 mRNAs with similarity to the kidney transcriptome. Thirteen upregulated genes predominantly expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis were found in T1D DKD groups. We constructed a transcriptional stress score based on six of these genes (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB), which reflected long-term decline of kidney function and could identify individuals with early decline even in normoalbuminuric patients.