Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease
Om Prakash Dwivedi, Karina Barreiro, Annemari Käräjämäki, Erkka Valo, Anil K. Giri, Rashmi B. Prasad, Rishi Das Roy, Lena M. Thorn, Antti Rannikko, Harry Holthöfer, Kim M. Gooding, Steven Sourbron, Denis Delić, Maria F. Gomez, Per‐Henrik Groop, Tiinamaija Tuomi, Carol Forsblom, Leif Groop, Maija Puhka
Abstract
Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 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 transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed 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 score" that reflected long-term decline of kidney function and could even identify normoalbuminuric 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.