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Abstract: TH-PO547

Effect of PARP Inhibition on the Development of Vascular Calcification (VC) in CKD Rats

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Neven, Ellen, University of Antwerp, Antwerp, antwerp, Belgium
  • D'Haese, Patrick, University of Antwerp, Antwerp, antwerp, Belgium
  • Shanahan, Catherine M., King's College London, LONDON, United Kingdom
  • Duer, Melinda, University of Cambridge, Cambridge, United Kingdom
  • Harrison, James A., Cycle Pharmaceuticals, Cambridge, United Kingdom
  • Verhulst, Anja, University of Antwerp, Antwerp, antwerp, Belgium
Background

A new therapeutic approach for VC consists in the use of molecules directly interfering with the calcification process. Potential candidates for this are Poly ADP Ribose Polymerase (PARP) inhibitors. Through the understanding of PARP/PAR processes that occur in new bone formation, it has recently been discovered that VC is also mediated by PARP/PAR processes that release PAR from dying cells in the vascular wall. We evaluated the effect of the PARP inhibitor minocycline (MC) on the development of VC in a rat model with adenine-induced CKD.

Methods

56 male Wistar CKD rats were randomly assigned to 4 study groups (n=14 each) and treated daily during 6 wks with either tap water (CKD-Veh) or MC at doses of 5, 10 or 50 mg/kg respectively. MC treatment was initiated 1 wk after the start of adenine dosing (0.75% in diet during 4 wks). VC was evaluated by measuring arterial calcium (Ca) content as well as area % Von Kossa positivity. Bone status was evaluated by quantitative histomorphometric analysis of static and dynamic bone parameters.

Results

Mortality was limited as only 1 animal died before the study end. MC did not impact renal dysfunction nor did it affect PTH, phosphorus, Ca or FGF-23 levels. Arterial Ca content as well as area % Von Kossa positivity, indicated MC treatment to dose dependently decrease calcification in the aorta, carotid and femoral arteries which became significant in the 50 mg/kg group. Compared to CKD-Veh rats MC treatment went along with a tendency towards a lower bone area which however, was inversely associated with the MC dose and was abolished when the mineralized area over bone area was considered. Similar patterns were observed for the bone formation and mineral apposition rates respectively. No significant effect of MC treatment on the number of osteoblasts and osteoclasts was observed.

Conclusion

MC treatment reduced VC without affecting renal function and associated mineral disturbances, suggesting a direct and local action on the arterial wall. The beneficial effects on the vasculature reveal that PARP inhibition might be a promising, safe and effective treatment of VC. Further studies are warranted to get a more profound insight in the potential effects of MC on bone.

Funding

  • Commercial Support