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Kidney Week

Abstract: PO0611

Essential Renal Tubular Proteins Are Lost by Excretion Within Novel Large Extracellular Vesicles During Chronic Renal Insufficiency

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Adam, Ryan J., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Paterson, Mark, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Hoffmann, Brian R., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Kriegel, Alison J., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

Within weeks of surgery, the 5/6 nephrectomy (5/6Nx) rat spontaneously develops renal disease including tubular damage, brush border loss, and the production of very large extracellular vesicles present in the tubule lumen. These large renal tubule extracellular vesicles (LRT-EVs) are too large to be microsomes or exosomes, and lack markers of apoptotic bodies, and thus may represent an undescribed vesicle. We hypothesized that formation and excretion of these vesicles represents a pathological mechanism by which important tubule proteins are lost in chronic renal insufficiency.

Methods

We performed a longitudinal, histologic examination for the presence of LRT-EVs in renal tubules of 5/6Nx and sham-operated rats, and a proteomic analysis of LRT-EVs isolated from 5/6Nx rat urine 10 weeks following surgery.

Results

Histologic examination revealed virtually no LRT-EVs in sham-operated rat tubules at any time point. LRT-EVs were present in 5/6Nx rat tubules at all measured time points including 2, 4, 5, 7, and 10 weeks post-surgery, and exhibited a marked increase in percentage of tubule presence between week 5 (7.0 ± 2.7%) and week 7 (51.1 ± 6.5%). This increase temporally corresponds to a time of rapid progression of renal disease. Median LRT-EV diameter upon microscopic image analysis was 2.5 µm. Proteomic analysis of isolated LRT-EVs revealed them to contain a wide array of functionally essential tubule proteins including but not limited to basolateral Na+/K+ ATPase subunits, sodium-glucose co-transporters, aquaporin 1, megalin, cubilin, and mitochondrial VDAC.

Conclusion

Loss of important tubule proteins through production and urine-excretion of previously unreported LRT-EVs may represent a hitherto unappreciated aspect of chronic renal insufficiency.

Funding

  • Other NIH Support