Kidney Week

Abstract: FR-PO702

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

Session Information

• Dialysis: Vascular Access - I
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 704 Dialysis: Vascular Access

Authors

• Shiu, Yan-Ting, University of Utah, SALT LAKE CITY, Utah, United States

Yan-Ting Shiu,

• Le, Ha Do, University of Utah, SALT LAKE CITY, Utah, United States

Ha Do Le,

• He, Yuxia, University of Utah, SALT LAKE CITY, Utah, United States

Yuxia He,

• Tey, CS Jason, University of Utah, SALT LAKE CITY, Utah, United States

CS Jason Tey,

• Falzon, Isabelle Dorothy, University of Utah, SALT LAKE CITY, Utah, United States

Isabelle Dorothy Falzon,

• Zhang, Yanhang, Boston University, Boston, Massachusetts, United States

Yanhang Zhang,

• Allon, Michael, University of Alabama at Birmingham, Birmingham, Alabama, United States

Michael Allon,

• Lee, Timmy C., University of Alabama at Birmingham, Birmingham, Alabama, United States

Timmy C. Lee,

• Berceli, Scott A., University of Florida, Gainesville, Florida, United States

Scott A. Berceli,

• Nath, Karl A., Mayo Clinic, Rochester, Minnesota, United States

Karl A. Nath,

• Jaimes, Edgar A., Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Edgar A. Jaimes,

• Cheung, Alfred K., University of Utah, SALT LAKE CITY, Utah, United States

Alfred K. Cheung,

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