Abstract: FR-PO158

Mitochondrial Protection Regulates Expression of Senescent Cell Regulators p16 and p21 in Parietal Epithelial Cells (PECs) of Aged Kidneys

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Sweetwyne, Mariya T., University of Washington, Seattle, Washington, United States
  • Rabinovitch, Peter S., University of Washington, Seattle, Washington, United States
  • Shankland, Stuart J., University of Washington, Seattle, Washington, United States
Background

Mitochondrial dysfunction increases with age and can induce cellular senescence. Kidneys are a mitochondrial rich tissue and show predictable pathological changes with age. We have previously demonstrated that systemic late-age treatment with the mitochondrial protective peptide SS-31 reduced age-induced glomerulosclerosis in mice of 24-28 months of age (~70-85 yr old human). Additionally, mitochondria-protected aged kidneys showed reduced podocyte injury, preservation of endothelial cell number and increased parietal epithelial cell density. Concomitant to these changes was a significant reduction in senescence-associated-β-galactosidase (SA-β-gal) expression across all compartments of the renal cortex. Staining for cell-cycle senescence regulator, p16 increased with age, but with SS-31 treatment was reduced in both PECs and the glomerular tuft of aged mice relative to aged baseline.

Results

In our current studies we further characterized PEC senescence by staining for expression of p21. Expression of p21 in PECs demonstrated an inverse relationship to that of p16 (p21 young =57.48% vs. aged vehicle =20.08% vs. aged SS-31 =31.46%; p16 young =11.9% vs. aged vehicle =55.0% vs. aged SS-31 =29.6%). Furthermore, expression of p21 in tuft cells did not change with either age or treatment. Close examination of glomeruli in serial sections showed a differential expression of p16 and p21 in PECs along Bowman’s capsule, with individual PECs expressing either p16 or p21, but not both. To determine if senescence in PECs could be directly regulated by mitochondrial damage, we exposed immortalized mouse PECs (mPEC) to mitochondrial insult via low doses (5,15, 20 nM) of Rotenone, Oligomycin A and Antimycin A. After 3d exposure, mitochondrial injury and oxidative stress increased in cells with mid and high doses of all treatments, as detected by MitoTrackerFR and CellRox green respectively. At 2 weeks of culture, 20 nM Rotenone increased expression of SA-β-gal in mPECs. In the treated cells, p16 but not p21 nuclear expression increased by immunocytochemistry.

Conclusion

Late-age SS-31 intervention amelorates renal mitochondrial damage and senecence. In the glomeruli of aged mice and in cell culture, mitochondrial dysfunction corresponds to PEC senescence with increased expression of p16 but not p21.

Funding

  • NIDDK Support