ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO702

Roles of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Arteriovenous Fistula (AVF) Development

Session Information

Category: Dialysis

  • 704 Dialysis: Vascular Access

Authors

  • Shiu, Yan-Ting, University of Utah, SALT LAKE CITY, Utah, United States
  • Le, Ha Do, University of Utah, SALT LAKE CITY, Utah, United States
  • He, Yuxia, University of Utah, SALT LAKE CITY, Utah, United States
  • Tey, CS Jason, University of Utah, SALT LAKE CITY, Utah, United States
  • Falzon, Isabelle Dorothy, University of Utah, SALT LAKE CITY, Utah, United States
  • Zhang, Yanhang, Boston University, Boston, Massachusetts, United States
  • Allon, Michael, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Lee, Timmy C., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Berceli, Scott A., University of Florida, Gainesville, Florida, United States
  • Nath, Karl A., Mayo Clinic, Rochester, Minnesota, United States
  • Jaimes, Edgar A., Memorial Sloan-Kettering Cancer Center, New York, New York, United States
  • Cheung, Alfred K., University of Utah, SALT LAKE CITY, Utah, United States
Background

Collagen is one of the most abundant vascular extracellular matrix components, and collagenolytic MMP-2 and MMP-9 are key regulators of vascular remodeling. MMP-2 and MMP-9 are known to stimulate the proliferation of vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and cause collagen disruption. These properties may respectively promote the formation of neointimal hyperplasia (NH) and alter the ability of the AVF wall to expand in patients with chronic kidney disease (CKD). Thus, we investigated the effect of CKD on MMP-2 and MMP-9 expression, and their roles in AVF development.

Methods

Human vascular ECs and SMCs were cultured in serum obtained from CKD patients or non-CKD control subjects and then quantified for MMPs by western blot. We used a modified low-dose adenine diet to induce CKD in Wistar rats. Baseline femoral venous MMPs were quantified and femoral AVFs were created in CKD rats and non-CKD rats. Baseline vascular compliance was measured and carotid-jugular AVFs were created in global MMP-2 or MMP-9 knockout (KO) mice on C57BL/6 background, with C57BL/6 mice serving as wild-type (WT) controls. AVFs from both animal models were harvested for histology.

Results

Compared to non-CKD serum, CKD serum enhanced MMP-2 (1.3-fold) and MMP-9 (20-fold) protein expression in cultured ECs. Similar trends were found for SMCs. When compared to non-CKD rats, CKD rats had higher baseline venous MMP-2 (3-fold) and MMP-9 (4-fold), and smaller AVF vein lumen area 4 weeks after creation. Baseline carotid arteries from the MMP-2 KO mice and MMP-9 KO mice had higher compliance when compared to WT mice. The percent open lumen area of the AVF veins at 1 week after creation was larger in the MMP-2 KO mice (39% ± 6%) and MMP-9 KO mice (47% ± 3%) vs. the WT mice (11% ± 2%).

Conclusion

Our animal studies showed that MMP-2 and MMP-9 were strong impediments to AVF development. Therapeutic approaches of inhibiting these molecules may enhance AVF maturation in CKD patients.

Funding

  • NIDDK Support