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Abstract: FR-PO468

Development of Senescence in the Rat Arteriovenous Fistula: Functional Effects of Heme

Session Information

  • Dialysis: Vascular Access
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

  • 803 Dialysis: Vascular Access

Authors

  • Croatt, Anthony J., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Grande, Joseph P., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Ackerman, Allan W., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Singh, Raman Deep, 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

As shown in our previous studies, the murine arteriovenous fistula (AVF) model in the presence of CKD (AVF-CKD) evinces markers of senescence in the venous limb [Am J Physiol Renal Physiol. 315(5):F1493-F1499, 2018]. We now assess whether an AVF fashioned in the rat also exhibits senescence, and whether heme, a prosenescent agent, alters rat AVF function.

Methods

Subtotal nephrectomy was performed in rats after which an AVF was created by anastomosing the femoral artery and vein. At 1 and 2 weeks after AVF creation, the AVF was assessed for evidence of senescence, including increased expression of cell cycle inhibitors (p16 and p21), senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated secretory phenotype (SASP) factors. In additional studies, the effect of heme on AVF blood flow was assessed in the rat.

Results

One week after AVF creation, p16 and p21 mRNA levels were markedly elevated in AVF veins compared to sham veins, as were p21 protein levels; p21 protein in the AVF artery was also increased. At 2 weeks, p21 protein was again upregulated in the AVF vein and artery, and protein levels of p53, an upstream inducer of p21, were significantly increased in the AVF artery, and tended to be higher in the AVF vein (p = 0.083). Upregulation of SASP factors was also observed in the AVF vein at 1 week; PAI-1, IL-6, TNF-α and MCP-1 mRNA were all markedly induced compared with sham values. At this time point, miR21, (associated with vascular senescence) was also elevated in the AVF vein. Additionally, SA-β-Gal activity, an established senescence marker, was significantly increased in both the artery and vein compared to their sham counterparts at 1 and 2 weeks post AVF surgery. Finally, heme administration increased AVF blood flow at 5 days after AVF placement, but resulted in lower AVF flow rates at 3 weeks.

Conclusion

We demonstrate that the rat AVF in the presence of CKD exhibits a senescent phenotype, akin to the murine AVF-CKD model. We suggest that heme, administered over 3 weeks, reduces AVF blood flow because of its prosenescent inflammatory effects whereas an early increase in AVF blood flow results from vasodilation that this agent can induce. These results point to the need to further investigate the role of senescence in AVF function/dysfunction, and the biphasic effects of heme treatment.

Funding

  • NIDDK Support