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Abstract: SA-PO434

Hypoxia Preconditioning Modifies Mesenchymal Stem Cell Senescence and Epigenetics Mechanisms in Experimental Atherosclerotic Renal Artery Stenosis

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Isik, Busra, Mayo Clinic, Rochester, Minnesota, United States
  • Bacik Goksu, Busra Nur, Mayo Clinic, Rochester, Minnesota, United States
  • Conley, Sabena, Mayo Clinic, Rochester, Minnesota, United States
  • Abumoawad, Abdelrhman, Mayo Clinic, Rochester, Minnesota, United States
  • Zhu, Xiang yang, Mayo Clinic, Rochester, Minnesota, United States
  • Eirin, Alfonso, Mayo Clinic, Rochester, Minnesota, United States
  • Hickson, LaTonya J., Mayo Clinic, Rochester, Minnesota, United States
  • Van wijnen, Andre J., Mayo Clinic, Rochester, Minnesota, United States
  • Textor, Stephen C., Mayo Clinic, Rochester, Minnesota, United States
  • Lerman, Lilach O., Mayo Clinic College of Medicine, Rochester, Minnesota, United States
  • Herrmann, Sandra, Mayo Clinic, Rochester, Minnesota, United States
Background

Atherosclerotic Renal Artery Stenosis(ARAS) is a contirbutor for hypertensive nephropathy(HN). Autologous mesenchymal stem cells(MSCs) is a promising therapy for ischemic nephropahty in patients with ARAS. However,MSCs from older ARAS patients are associated with impaired function, senescence, and DNA damage,possibly due to epigenetic mechanisms.Hypoxia preconditioning(HPC) exhibits beneficial effects on cellular proliferation,differentiation, as well as gene and protein expression.We hypothesized that HPC could influence MSC function, senescence and epigenetic mechanisms by modulating chromatin-modifying enzymes.

Methods

MSCs harvested from subcutaneous abdominal fat tissue of healthy(N=5) or ARAS(N=8)pigs were cultured under normoxia(20%O2)or hypoxia(1%O2) until 70-80% confluence.MSC function was measured by migration and proliferation assays,as well as cytokine levels in conditioned media.MSC senescence was evaluated by SA-β-gal activity and epigenetic markers, including HDAC activity and DNA hydroxymethylation using dot blot analysis.

Results

MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased VEGF and IGF levels than normoxia-cultured MSCs(Figure). Under basal conditions,dot blot analysis showed lower DNA hydroxymethylation in ARAS.During HPC, MSC HDAC activity increased whereas DNA hydroxymethylation decreased, suggesting broad epigenetic changes.Furthermore,SA-β-gal activity fell, indicating lower senescence burden on HPC-MSCs.

Conclusion

HPC mitigates autologous MSC dysfunction,decreased MSC senescence and DNA hydroxymethylation in ARAS pigs.Future studies are needed to determine the effect of HPC in MSCs of patients with other vascular nephropathies to optimize the potential use of autologous MSC therapy in this population.

Funding

  • NIDDK Support