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Abstract: TH-OR076

Renal Artery Stenosis Induces Renal Cellular Senescence

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Kim, Seo Rin, Mayo Clinic , Rochester, Minnesota, United States
  • Puranik, Amrutesh, Mayo Clinic , Rochester, Minnesota, United States
  • Jiang, Kai, Mayo Clinic , Rochester, Minnesota, United States
  • Ferguson, Christopher M., Mayo Clinic , Rochester, Minnesota, United States
  • Hickson, LaTonya J., Mayo Clinic , Rochester, Minnesota, United States
  • Tchkonia, Tamara, Mayo Clinic, Rochester, Minnesota, United States
  • Kirkland, James L., Mayo Clinic, Rochester, Minnesota, United States
  • Lerman, Lilach O., Mayo Clinic , Rochester, Minnesota, United States
Background

Cellular senescence (CS) is an irreversible proliferation arrest with secretory phenotype evoked in response to stress, which can be identified by upregulation of the cyclin-dependent kinase inhibitor p16INK4a. Renal artery stenosis (RAS) induces stenotic kidney (STK) ischemia and injury, but whether these involve activation of CS remains unclear. We studied CS in the STK of transgenic INK-ATTAC mice, in which p16 INK4a-expressing cells can be selectively eliminated by injection of AP20187.

Methods

INK-ATTAC mice were randomized to a 4-week treatment with AP20187 (3.3μg/g, IP, 3/week) or vehicle starting after 2 weeks of RAS or sham (n=6-8 each). Single kidney function (GFR) and oxygenation were studied in vivo using 16.4T magnetic resonance imaging at baseline and 6 weeks after surgery. CS was assessed by plasma levels of Activin-A, and by image cytometry analysis of p16 INK4a-positive cells in dissociated kidney tissue.

Results

After 6 weeks of RAS blood pressure, Activin-A, STK tissue hypoxia were all elevated, and plasma creatinine tended to be higher compared to sham, whereas STK RBF and GFR were decreased. The percentage of p16 INK4a-positive cells increased in the STK, many of which expressed epithelial, but not endothelial, cell markers (Fig. E). Clearance of p16 INK4a-positive cells restored blood pressure, Activin-A, and plasma creatinine levels, and prevented the fall in GFR, and rise in tissue hypoxia (Fig. A-D), whereas RBF remained unchanged.

Conclusion

Renal artery stenosis induces cellular senescence in the stenotic kidney, particularly in tubular epithelial cells, and their clearance improves renal function. These observations suggest a role for cellular senescence in pathogenesis of renal artery stenosis, supporting development of senotherapy.

Funding

  • NIDDK Support