Abstract: FR-OR090
Inhibition of MicroRNA-92a Enhances Arteriovenous Fistula Development
Session Information
- Improving Vascular Access Outcomes
October 26, 2018 | Location: 6B, San Diego Convention Center
Abstract Time: 04:54 PM - 05:06 PM
Category: Dialysis
- 704 Dialysis: Vascular Access
Authors
- Shiu, Yan-Ting, University of Utah, Salt Lake City, Utah, United States
- Tey, CS Jason, University of Utah, Salt Lake City, Utah, United States
- He, Yuxia, University of Utah, Salt Lake City, Utah, United States
- Le, Ha Do, University of Utah, Salt Lake City, Utah, United States
- Falzon, Isabelle Dorothy, University of Utah, Salt Lake City, Utah, United States
- Chen, Zhen, City of Hope, Duarte, California, United States
- Fang, Yun, University of Chicago, Chicago, Illinois, United States
- Lesniewski, Lisa, University of Utah, Salt Lake City, Utah, United States
- Cheung, Alfred K., University of Utah, Salt Lake City, Utah, United States
Background
The Hemodialysis Fistula Maturation Consortium Study showed that endothelial health was associated with the development of arteriovenous fistulas (AVFs). MicroRNA (MiR)-92a is a major contributor to vascular endothelial dysfunction. We recently reported that patients with chronic kidney disease (CKD) had increased serum miR-92a levels when compared to non-CKD control subjects, and that serum miR-92a was likely derived from the endothelium. Thus, we investigated the relationship between miR-92a and AVF development in animal models.
Methods
In young male Wistar rats with normal kidney function or with adenine diet-induced CKD, we created femoral AVFs and then assessed AVF lumen diameter by ultrasound and AVF tissue miR-92a levels by RT-PCR at 4 weeks after creation. In a mouse carotid-jugular AVF model, miR-92a inhibition was achieved using genetic and pharmacological approaches: (1) whole-body knockout (miR-92a−/−) with C57BL/6 mice used as wild-type (WT) controls; or (2) nanoparticles (NPs) that encapsulate miR-92a inhibitors and target inflamed endothelium (un-encapsulated miR-92a inhibitors and saline were used as no-NP and no-treatment controls, respectively). C57BL/6 mice received the inhibitor treatment (8 mg/kg body weight) intravenously at 1 day after AVF creation and were sacrificed 1 week later. Mouse AVF cross-sectional lumen area was quantified by histology.
Results
When compared to AVFs in non-CKD rats, AVFs in CKD rats had increased miR-92a expression (3-fold, p<0.05) and smaller AVF lumen diameter (1.0 ± 0.51 in CKD vs. 1.55 ± 0.65 mm in non-CKD, p<0.05). In the knockout study, the percent open lumen area of AVF veins was larger in miR-92a−/− mice (72% of total area) than in WT mice (12%). In the inhibitor study, both NP-encapsulated (41%) and un-encapsulated (23%) miR-92a inhibitors resulted in larger open lumen area than saline control (5%), and the effect of encapsulated inhibitors was more pronounced.
Conclusion
In our rat model, CKD increased the AVF tissue miR-92a levels and decreased the AVF lumen area. Further, inhibition of miR-92a improved AVF development. Nanomedicine may offer a novel and effective therapeutic approach to enhance AVF maturation in CKD patients.
Funding
- NIDDK Support