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Abstract: SA-PO253

Exosomal or Non-Exosomal Profiles: Origin of Circulating miRNAs Associated With ESKD in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Nowak, Natalia Z., Joslin Diabetes Center, Boston, United States
  • Md Dom, Zaipul I, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Kobayashi, Hiroki, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Ricca, Joseph, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Krolewski, Bozena, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Pezzolesi, Marcus G., University of Utah, Salt Lake City, Utah, United States
  • Kahn, Ronald, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

microRNAs (miRNAs) are 22 nt non-coding RNA molecules that can regulate gene and protein expression both in the cells that produce them and, potentially, in distant cells acting via secretion into the circulation. Previously, we identified 17 miRNAs in plasma that were either positively (risk) or negatively (protection) associated with progression to ESKD (JASN 2021). To elucidate possible mechanisms of transport of these miRNAs in the circulation, we compared levels of these miRNAs in plasma with their levels in exosomes.

Methods

Plasma from 55 T1D patients was divided into 11 pools (5 patients per pool), and exosomes isolated using size exclusion chromatography. miRNA levels in the 11 plasma and exosome pools were then assessed using the HTG EdgeSeq platform. The data were quantile normalized and analyzed using the R packages edgeR and limma.

Results

Out of 2083 miRNAs on the HTG platform, 463 (22%) were detected only in plasma, 72 (3%) were only in exosome, while 1358 were detected in both specimens. Of these, 437 (21%) had significantly higher (fold-change >2 and p<3.7x10-5) concentrations in exosomes than in plasma, 402 miRNAs (19%) were higher in plasma than in exosomes, and 519 (25%) were similar in both specimens. All of the 17 ESKD-associated miRNAs were detected in both specimens, however, the relationship between concentration in exosomes and plasma were different between protective and risk miRNAs. Among the 9 protective miRNAs, 4 had similar concentration in plasma and exosomes, and 5 were significantly higher in plasma than in exosomes. Among the 8 risk miRNAs, all had low concentrations in exosomes and dramatically higher (5–400 fold) in plasma.

Conclusion

This study shows that the majority of the ESKD-associated miRNAs have low concentrations in exosomes but very high in plasma, indicating that the ESKD-associated miRNAs are present mainly in non-exosomal plasma fraction. Mechanisms of their release into circulation and uptake by target tissue(s) are unknown but differ from those for the miRNAs transported mainly in exosomes. Understanding how these non-exosomal miRNAs are secreted and act on the kidney should provide new insights into the mechanism of the progression of diabetic kidney disease to ESKD and its possible treatment.

Funding

  • NIDDK Support