β,γ-methylene-ATP and its metabolite medronic acid affect both arterial media calcification and bone mineralization in non-CKD and CKD ratso

Abstract

Arterial media calcification or pathological deposition of calcium-phosphate crystals in the vessel wall contributes significantly to the high mortality rate observed in patients with chronic kidney disease (CKD). Extracellular nucleotides (i.e. ATP or UTP) regulate the arterial calcification process by interacting with (i) purinergic receptors and (ii) breakdown via ecto-nucleotidases such as NPP1 or NPP3 affecting the local levels of calcification inhibitor, pyrophosphate, and –stimulator inorganic phosphate (PPi/Pi ratio). Also, it has been shown that ATP analogs (i.e. β,γ-meATP) inhibit vascular smooth muscle cell calcification in vitro. In the first experiment, daily dosing of β,γ-meATP (2 mg/kg) was investigated in rats, receiving a warfarin diet to trigger the development of non-CKD related arterial medial calcifications. This study showed that β,γ-meATP significantly lowered the calcium scores in the aorta and peripheral vessels in warfarin-exposed rats. In a second experiment, daily dosing of 4 mg/kg β,γ-meATP, and its metabolite medronic acid (MDP) was analyzed in rats receiving an adenine diet to promote the development of CKD-related arterial medial calcification. β,γ-meATP, and MDP did not significantly decrease aortic calcification scores in this model. Moreover, both compounds induced deleterious effects on physiological bone mineralization causing an imminent risk for worsening the already compromised bone status in CKD. Due to this, it was not possible to raise the dosage of both compounds to tackle CKD-related arterial calcification. Again, this points out the difficult task; targeting solely ectopic calcifications without negatively affecting physiological bone mineralization. On the other hand, aortic mRNA expression of Enpp1 and Enpp3 was significantly and positively associated with aortic calcification scores, suggesting that normalizing the aortic NPP1/3 activity to control values might be a possible target to treat (CKD-induced) arterial media calcifications.