Abstract: TH-OR111

The Impact of a Young Circulation on Renal Injury and Fibrosis in Aged Mice

Session Information

  • Scarred for Life?
    November 02, 2017 | Location: Room 394, Morial Convention Center
    Abstract Time: 05:06 PM - 05:18 PM

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Ferenbach, David A., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Xin, Cuiyan, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Wilflingseder, Julia, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Hughes, Jeremy, University of Edinburgh, Edinburgh, Edinburgh, United Kingdom
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Aging is associated with an increased risk of acute kidney injury (AKI) and higher rates of subsequent fibrotic chronic kidney disease (CKD). The mechanisms accounting for these changes in injury and fibrosis susceptibility remain poorly understood. We conducted studies using heterochronic parabiosis to test whether the young circulation can influence injury imposed on an older mouse.

Methods

Parabiotic pairs were established between young (Y, 8 weeks old) and old (O, 14 months old) female C57BL6 mice to generate YY, OO, OY and YO pairings, and a shared microcirculation was allowed to develop for 28 days. Baseline and post-injury renal characteristics were assessed by immunofluorescence, western blotting, microarray analysis and Somascan measurement of circulating protein levels. AKI was induced via 20 minutes bilateral renal ischaemia/reperfusion injury (IRI), and chronic fibrosis via unilateral ureteric obstruction. Animals were followed for 24hrs for peak IRI severity, and for up to 14 days for UUO-induced fibrosis

Results

Baseline renal function was equivalent in all groups. At d28 of parabiosis, old animals in both OO and OY pairings had increased levels of baseline fibrosis (p<0.05) compared to the young in YO and YY pairs. In the acute injury model on the Old mice, OY animals demonstrated significantly lower 24 hr serum creatinine compared with OO animals (p<0.05). In the UUO model of chronic renal fibrosis, Old animals in OY pairs showed reduced scarring, macrophage infiltration and inflammatory gene transcription compared to Old paired with Old mice (OO) (all p<0.05). Microarray studies revealed multiple transcriptional processes which alter with aging and injury and revert to 'young' patterns after OY pairing. Bulk proteomics on >1000 circulating proteins identified 11 compounds which track with the protected phenotype.

Conclusion

Our data show that normal aged kidneys exhibit differences from the young kidney at a transcriptomic and proteomic level even with well maintained renal function. Furthermore, connection to a young circulation modifies the transcriptional signature in the aged kidney at baseline and protects against subsequent AKI and progressive renal scarring, indicating the presence of a circulating factor which modifies renal aging. Therapeutic targeting of these compounds is ongoing.

Funding

  • Private Foundation Support