Deletion of the P2Y(2) receptor aggravates internal elastic lamina calcification in chronic kidney disease mice through upregulation of alkaline phosphatase and lipocalin-2

Opdebeeck, B; Huysmans, I; van den Branden, A; Orriss, IR; D'Haese, PC; Verhulst, A

Abstract

Calcification of the medial layer, inducing arterial stiffness, contributes significantly to cardiovascular mortality in patients with chronic kidney disease (CKD). Extracellular nucleotides block the mineralization of arteries by binding to purinergic receptors including the P2Y(2) receptor. This study investigates whether deletion of the P2Y(2) receptor influences the development of arterial media calcification in CKD mice. Animals were divided into: (i) wild type mice with normal renal function (control diet) (n = 8), (ii) P2Y(2)R(-/-) mice with normal renal function (n = 8), (iii) wild type mice with CKD (n = 27), and (iv) P2Y(2)R(-/-) mice with CKD (n = 22). To induce CKD, animals received an alternating (0.2-0.3%) adenine diet for 7 weeks. All CKD groups developed a similar degree of chronic renal failure as reflected by high serum creatinine and phosphorus levels. Also, the presence of CKD induced calcification in the heart and medial layer of the aortic wall. However, deletion of the P2Y(2) receptor makes CKD mice more susceptible to the development of calcification in the heart and aorta (aortic calcium scores (median +/- IQR), CKD-wild type: 0.34 +/- 4.3 mg calcium/g wet tissue and CKD-P2Y(2)R(-/-): 4.0 +/- 13.2 mg calcium/g wet tissue). As indicated by serum and aortic mRNA markers, this P2Y(2)R(-/-) mediated increase in CKD-related arterial media calcification was associated with an elevation of calcification stimulators, including alkaline phosphatase and inflammatory molecules interleukin-6 and lipocalin 2. The P2Y(2) receptor should be considered as an interesting therapeutic target for tackling CKD-related arterial media calcification.

Citation

Opdebeeck, B., Huysmans, I., van den Branden, A., Orriss, I., D'Haese, P., & Verhulst, A. (2023). Deletion of the P2Y(2) receptor aggravates internal elastic lamina calcification in chronic kidney disease mice through upregulation of alkaline phosphatase and lipocalin-2. FASEB Journal, 37(1), https://doi.org/10.1096/fj.202201044R

• Journal Article Type: Article
• Acceptance Date: Nov 28, 2022
• Online Publication Date: Dec 15, 2022
• Publication Date: 2023
• Deposit Date: Aug 24, 2023
• Print ISSN: 0892-6638
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 37
• Issue: 1
• DOI: https://doi.org/10.1096/fj.202201044R
• Keywords: acute phase signaling; alkaline phosphatase; arterial media calcification; chronic kidney disease; purinergic signaling; ENZYME-REPLACEMENT THERAPY; VALVE INTERSTITIAL-CELLS; SMOOTH-MUSCLE-CELLS; EXTRACELLULAR NUCLEOTIDES; BONE MINERALIZATION; CORONARY; P