Stress markers in diabetic kidney disease exposed in urinary vesicles

New research shows that urinary extracellular vesicles provide a transcriptomic stress score that may help in early detection of diabetic kidney disease.

A group of scientists at FIMM, University of Helsinki, has discovered a novel stress gene signature from small extracellular vesicles (EV) in urine. The study is part of the international BEAt-DKD project.

The team, including Dr. Om Prakash Dwivedi, Dr. Maija Puhka and M.Sc. Karina Barreiro from the Institute for Molecular Medicine Finland (FIMM), set out to discover whether urine EV could provide a new source of biomarkers for the early detection of diabetic kidney disease.

Including over 150 individuals with type 1 or 2 diabetes, the study showed that the signature can recognize early signs of kidney distress. The discovery is significant, because the currently used clinical tests (albuminuria and glomerular filtration rate GFR) only detect a later stage of kidney damage.

Dr. Maija Puhka looks back at the start of the project: “We knew that urine EV originate from urogenital tract tissues including kidney. Kidney tissue biopsies offer the most accurate diagnosis, but they carry significant risks for the patients. Thus, we set out to explore urine EV as a liquid kidney biopsy.”

The team mapped the full mRNA content of EV in clinical urine samples from individuals with type 1 diabetes, and compared the results from patients with and without kidney disease. This analysis revealed mRNAs involved in mitigating the cellular stress in kidney.

“We used information from six upregulated genes to develop a transcriptomic score, which reflected long-term decline in kidney function. This urine stress score could alert of stress in the kidney during diabetes”, says Dr. Dwivedi.

In the project, he further developed tissue and kidney single cell level mapping that suggested a prominent kidney and proximal tubular cell origin of urinary EV. The study also showed association of the stress score with high blood glucose levels (hyperglycemia), a known causative factor of kidney disease.

“This finding was very fitting since we know that proximal tubular cells are sensitive to oxidative stress caused by high blood glucose”, says Professor Per-Henrik Groop, the leader of the FinnDiane Study.

The study provided some clinically promising findings. Interestingly, the stress score was higher in individuals who showed a declining trend of kidney function, but were not yet diagnosed with kidney disease based on clinical biomarkers.

 “There is definitely a high need for biomarkers allowing early interventions. Our initial replication results in both early and late disease stages look promising and larger validation studies are currently ongoing” Professor Tiinamaija Tuomi, the PI of the Direva study, explains.

The study utilized next generation sequencing of mRNAs set up for EV earlier in the project, in collaboration with the FIMM Technology centre HiPREP, EV and sequencing units. However, combining samples from three different diabetes studies - FinnDiane, DIREVA and iBEAt – with variable sample handling protocols required further development of the pipelines, quality criteria, and demonstration of the technological robustness.

The publication “Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease” is now available in iScience.

The study was supported by the Academy of Finland and by BEAt-DKD project funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974 supported by European Union’s Horizon 2020 research and innovation programme and EFPIA and JDRF.

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