Abstract: TH-PO297
Aging and Arteriovenous Fistula Remodeling in a Mouse Model
Session Information
- Vascular Access: From Biology to Managing Complications
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Vascular Access
Authors
- Fairbourn, Brayden, The University of Utah, Salt Lake City, Utah, United States
- Oumar, Amani, The University of Utah, Salt Lake City, Utah, United States
- Knysheva, Marina, The University of Utah School of Medicine, Salt Lake City, Utah, United States
- He, Yuxia, The University of Utah, Salt Lake City, Utah, United States
- Lesniewski, Lisa, The University of Utah, Salt Lake City, Utah, United States
- Donato, Tony J., The University of Utah, Salt Lake City, Utah, United States
- Cheung, Alfred K., The University of Utah, Salt Lake City, Utah, United States
- Shiu, Yan-Ting Elizabeth, The University of Utah, Salt Lake City, Utah, United States
Background
Arteriovenous fistulas (AVFs) are the preferred type of hemodialysis vascular access, but up to 60% fail to mature, i.e., have sufficiently large vein lumen area and blood flow. This failure rate is higher in old than young patients, and yet the biology of AVF remodeling has not been studied in the context of aging. To investigate the effects of aging on AVF development, we focused on the mammalian target of rapamycin (mTOR) and sirtuin-1 (SIRT1), two primary regulators of aging and arterial functions. We hypothesized that aging-related increased mTOR and decreased SIRT1 in the veins impair AVF development in old mice.
Methods
The protein levels of mTOR and SIRT1 in native external jugular veins (EJVs) of young (3 months) and old (18 months) C57BL/6 mice were determined by immunohistochemistry. Carotid-external jugular AVFs were created in young and old mice with or without treatment of either the mTOR inhibitor rapamycin (8 mg/kg) or the SIRT1 activator SRT1720 (100 mg/kg) by intraperitoneal injections (IPs). IPs began on the day of AVF creation and were repeated daily for rapamycin and twice a week for SRT1720 for 1 week until the mice were euthanized. Histological morphometry was used to quantify AVF % open lumen area and neointimal lesion area, and the transcriptomes were quantified by RNA sequencing.
Results
The protein level of mTOR increased approx. 2.4 fold and SIRT1 decreased approx. 3.4 fold from young to old EJVs. Without treatments, the % open lumen area in old (20±4%, n=3) was smaller than in young (48±3%, n=2) AVFs. The RNAseq data showed that collagen degradation and extracellular matrix organization were downregulated while fibrosis and inflammation were upregulated in old vs. young AVFs (n=3 each). In young AVFs, rapamycin increased the % open lumen areas to 74±13% (n=3), but STR1720 made no change (45±9%, n=4). In old AVFs, both treatments decreased neointimal lesion area approx. 1.9 fold and increased the % open lumen areas (rapamycin: 34±12%, n=3; SRT1720: 64±35%, n=3).
Conclusion
Our results suggest the potential of mTOR inhibition and SIRT1 activation to improve AVF maturation rates in patients of older age. With the population of older patients with end-stage kidney disease climbing quickly, it is imperative to develop methods to improve AVF maturation in older patients.
Funding
- NIDDK Support