Faculty Mentor: Yan-Ting Shiu (Internal Medicine, University of Utah)

Chronic kidney disease (CKD) affects about 15% of the adult population in the United States (U.S.) [1]. CKD has five stages, the last of which is called end-stage kidney disease (ESKD), or kidney failure, and requires transplantation or dialysis therapies. In the U.S., almost 70% of ESKD patients require hemodialysis for survival. The national costs of treatment for CKD are significant. In the U.S., one patient’s hemodialysis treatment costs $90,000 of Medicare expenditure per year [2]. For hemodialysis to function, a vascular access point must be created where blood is drawn from the body to the dialysis machine, cleaned, and then returned to the body. The most successful and economical vascular access option is the arteriovenous fistula (AVF) as it lasts the longest [2]. An AVF is surgically created by anastomosing the artery and vein, usually in an upper extremity [2]. After AVF creation, it must mature to become useful. Maturation failure often occurs in patients due to an excess of cell proliferation into the AVF’s lumen, called neointimal hyperplasia. When AVF maturation failure occurs, blood can no longer flow through the vascular access point and hemodialysis cannot occur. Neointimal hyperplasia occurs due to proinflammatory cytokines and adhesion molecules that are released after the vascular injury inherent to AVF creation surgery.

E26 transformation-specific sequence-1, or ETS-1, is an oncogene that has previously been associated with AVF maturation failure in a mouse model. The literature has previously established that ETS-1 causes neointima formation after endovascular injury by activating proinflammatory cytokines and adhesion molecules in a mouse model [3], [4], [5], [6]. This work investigates whether ETS-1 also causes neointima formation after AVF creation surgery in a rat model. This was done by observing the effects of ETS-1 gene knockout through histological analyses of ETS-1 knockout (KO) rats and wild-type (WT) rats with AVFs and induced CKD. Morphometric analysis was used to quantify the open lumen percentage of AVFs in all four groups. Between the four groups, no statistically significant difference in open lumen percentage was found at both the week 1 and week 4 timepoints, likely due to small sample sizes. Further translational research into inhibition of the ETS-1 pathway may be worthwhile and lead to the development of therapies for prevention of neointimal hyperplasia and promotion of successful AVF maturation. By investigating ETS-1 inhibition as a potential therapy for neointimal hyperplasia formation prevention, this research could lead to improved AVF maturation rates, reducing the need for revisit surgeries and enhancing the quality of life for CKD patients.

Reference

[1] “Chronic Kidney Disease Basics | Chronic Kidney Disease Initiative | CDC.” Accessed: May 09, 2024. [Online]. Available: https://wwwdev.cdc.gov/kidneydisease/basics.html

[2] A. M. Marsh, R. Genova, and J. L. Buicko Lopez, “Dialysis Fistula,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2024. Accessed: May 09, 2024. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK559085/

[3] W. Feng et al., “The Transcription Factor E26 Transformation–Specific Sequence-1 Mediates Neointima Formation in Arteriovenous Fistula,” J Am Soc Nephrol, vol. 25, no. 3, pp. 475–487, Mar. 2014, doi: 10.1681/ASN.2013040424.

[4] Y.-T. Shiu and E. A. Jaimes, “Transcription Factor ETS-1 and Reactive Oxygen Species: Role in Vascular and Renal Injury,” Antioxidants (Basel), vol. 7, no. 7, p. 84, Jul. 2018, doi: 10.3390/antiox7070084.

[5] H. M. Northrup, Y.-T. E. Shiu, C. J. Tey, Y. He, and E. A. Jaimes, “Roles of Matrix Metalloproteinase-2 and ETS Proto-Oncogene 1 in Rodent Arteriovenous Fistula Development: TH- OR47,” Journal of the American Society of Nephrology, vol. 34, no. 11S, p. 14, Nov. 2023, doi: 10.1681/ASN.20233411S114d.

[6] Y. Zhan et al., “Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling,” J Clin Invest, vol. 115, no. 9, pp. 2508–2516, Sep. 2005, doi: 10.1172/JCI24403.