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Abstract: PO0321

Amelioration of Uremic Vascular Calcification After Experimental Aorta Transplantation

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Mace, Maria Lerche, Rigshospitalet, Kobenhavn, Denmark
  • Egstrand, Søren, Rigshospitalet, Kobenhavn, Denmark
  • Nordholm, Anders, Rigshospitalet, Kobenhavn, Denmark
  • Morevati, Marya, Rigshospitalet, Kobenhavn, Denmark
  • Behets, Geert J., Universiteit Antwerpen, Antwerpen, Belgium
  • D'Haese, Patrick, Universiteit Antwerpen, Antwerpen, Belgium
  • Olgaard, Klaus, Rigshospitalet, Kobenhavn, Denmark
  • Lewin, Ewa, Herlev Hospital, Herlev, Denmark
Background

CKD causes a shift in phenotype of the vascular smooth muscle cell (VSMC) to a bone-like secretory cell and promotes vascular calcification (VC). Our aim was to study whether VC is reversed by transplantation of a uremic calcified aorta into a healthy recipient.

Methods

A novel model of isogenic aorta transplantation in the rat was used (ATx). VC was induced in inbred Dark Aguti rats by 5/6 nephrectomy, high phosphate diet and alfacalcidol treatment. The abdominal aorta of the uremic rat was transplanted into a normal rat (uremic ATx, n=16). Control groups were: ATx between normal rats (normal ATx, n=9) and age-matched rats (control, n=6). Four weeks after ATx, the aorta was analyzed for genes related to the osteochondrogenic transition by RT-qPCR. Data are presented as mean±SD. mRNA levels are normalized to stabile housekeeping genes and expressed as the ratio to control.

Results

The uremic donor rat had severe CKD with disturbed mineral and bone metabolism as well as severe aorta calcification with altered expression of genes related to the osteochondrogenic phenotype. ATx mitigated some of these genetic changes as indicated by a significant downregulation of the expression levels of mineralization inhibitors and fibrosis matrix proteins. More specifically, mRNA levels of MGP (control 1±0.18 vs. uremic 3.74±0.18 vs. uremic ATx 1.67±0.61), Spp1 (control 1±0.20 vs. uremic 13.69±4.47 vs. uremic ATx 2.62±0.84), ANKH (control 1±0.15 vs. uremic 10.43±6.90 vs. uremic ATx 4.49±1.72), Postn (control 1±0.34 vs. uremic 3.19±0.77 vs. uremic ATx 1.74±0.85), Fn1 (control 1±0.25 vs. uremic 7.26±2.49 vs. 3.02±1.45), all p<0.01. No difference in expression of these genes between control and normal ATx was noticed. The VSMC markers ACTA2 & Eln were downregulated in uremic VC with no recovery through ATx. The upregulated Wnt inhibitor sclerostin showed a trend towards downregulation by ATx. Activin A & TGF-beta were highly upregulated in uremic VC with no reversibility. Plasma biochemistry did not differ between control, normal ATx and uremic ATx.

Conclusion

Our results for the first time show downregulation of genes related to mineralization and fibrosis, indicating amelioration of uremic vasculopathy after experimental aorta transplanation.

Funding

  • Government Support - Non-U.S.