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Kidney Week

Abstract: FR-OR131

Endurance Exercise-Derived Exosomal miRNA Exerkines Attenuate Progressive CKD

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Tampe, Bjoern, University Medical Center Goettingen, Goettingen, Germany
  • Zeisberg, Michael, University Medical Center Goettingen, Goettingen, Germany
Background

Progressive CKD is still an unmet biomedical challenge because no effective therapies are available as of yet for clinical use. While various studies across multiple organs which demonstrated that endurance exercise (EE) protects from progressive organ failure by endocrine-like signalling via specific nucleic acids (so-called exerkines), little consideration has been paid as to whether any exerkines are released in a manner other than direct discharge into the circulation. It is becoming increasingly apparent that one of the main mechanisms by which scelettal muscle cells and distant organs communicate is by the release of cell-derived extracellular exosomes. Based on these pre-requisits, we here aimed to gain insights into the molecular mechanisms underlying successful reno-protection and to explore whether such pathways could be therapeutically targeted.

Methods

EE was performed in C57BL/6mice for 4 weeks before challenging with unilateral ureteral obstruction (UUO) for 7 days without EE. Exosomal miRNA signatures were analyzed by unbiased array-based approaches and confirmed by qRT-PCR in sclettal muscles, plasma exosomes and corresponding kidneys. By using miRNA mimics administered systemically, miRNA candidates for succesful protection during EE were confirmed for therapeutical implications.

Results

We identified a unique miRNA signature in muscle-derived exosomes and kidneys specifically during endurance exercise, associated with attenuation of progressive CKD. Systemic administration of miRNA mimics was equally effective to attenuate progressive CKD, supporting that endurance exercise-derived exosomal miRNAs are involved in reno-protection. On a mechanistic level, we provide evidence that exosomal miRNAs directly target and degrade PAI-1, associated with activation of the tPA/uPAR/plasmin pathway. Increased tPA/uPAR/plasmin stimulates ECM remodelling and degradation by activation of latent MMPs, in particular MMP-2 and MMP-9.

Conclusion

In summary, we here provide evidence that EE attenuates progressive CKD by enrichment of exosomal miRNA exerkines modulating ECM remodelling and degradation in chronically injured kidneys. Because miRNA mimics equally protect from progressive CKD, these findings further support therapeutical implications of exosomal exerkines as nature’s exercise pill.