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Abstract: PO1013

The Rat Arteriovenous Fistula in the Setting of CKD Displays a Senescence Phenotype

Session Information

Category: Dialysis

  • 703 Dialysis: Vascular Access

Authors

  • Croatt, Anthony J., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Grande, Joseph P., Mayo Clinic Department of Laboratory Medicine and Pathology, Rochester, Minnesota, United States
  • Ackerman, Allan W., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Nath, Karl A., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
Background

We previously demonstrated that the murine arteriovenous fistula model in the setting of CKD (AVF-CKD) exhibits a senescence phenotype including increased expression of hallmark cell cycle inhibitors, senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated secretory phenotype (SASP) factors, along with evidence of telomere erosion [Am J Physiol Renal Physiol. 315(5):F1493-F1499, 2018]. In the present study, we questioned whether this senescence phenotype exists in an AVF created in another species, namely the femoral AVF in the rat.

Methods

An end-vein to side-artery AVF was surgically created in the femoral vessels of rats which had previously been subjected to uremia via subtotal nephrectomy. At 1 and 2 weeks after AVF formation the arterial and venous limbs of the AVF were harvested for the assessment of gene and protein expression and the assay of SA-β-Gal activity. Femoral veins and arteries from rats subjected to sham surgery were used as controls.

Results

At 1 week after AVF creation mRNA levels of senescence drivers p16 and p21 were markedly elevated in AVF veins compared to sham veins, as were p21 protein levels; the AVF artery also displayed elevated p21 protein levels at this time point. At 2 weeks, p21 protein was again upregulated in both the vein and artery of the AVF, and protein levels of an upstream mediator in the p21 senescence pathway, p53, were significantly increased in the AVF artery; p53 levels did not achieve significance (p=0.083) in the AVF vein at this time point. Upregulation of SASP factors was also observed in the AVF vein at 1 week: mRNA expression of PAI-1, IL-6, TNF-α and MCP-1 was robustly increased as compared to sham veins at 1 week after AVF creation. Additionally, miR21, which has been associated with vascular senescence, was markedly elevated in the AVF vein at 1 week post AVF placement. Finally, SA-β-Gal activity, an established marker of senescence was significantly increased in both the artery and vein compared to their sham counterparts at both 1 and 2 weeks post AVF surgery.

Conclusion

Using established criteria, this study demonstrates that the rat femoral AVF in the setting of CKD has a senescence phenotype similar to the murine AVF-CKD model. These findings thus demonstrate the development of senescence in another species subjected to an AVF in the presence of uremia.

Funding

  • NIDDK Support