Apelin: A novel inhibitor of vascular calcification in chronic kidney disease

•Apelin inhibits high-phosphate induced osteogenic differentiation and calcification in HASMCs.•Apelin suppresses Pit-1 expression and phosphate uptake in HASMCs.•The serum apelin and APJ expression in the calcified aorta decrease in CKD rats.•Apelin increases urine phosphate excretion and reduces serum phosphate level in CKD rats.•Apelin normalizes the level of the apelin/APJ system and ameliorates aortic calcification.

BackgroundVascular calcification (VC) is closely related to cardiovascular events in chronic kidney disease (CKD). Apelin has emerged as a potent regulator of cardiovascular function, but its role in VC during CKD remains unknown. We determined whether apelin plays a role in phosphate-induced mineralization of human aortic smooth muscle cells (HASMCs) and in adenine-induced CKD rats with aortic calcification.Methods and resultsIn vitro, apelin-13 was found to inhibit calcium deposition in HASMCs (Pi+ Apelin+ group vs Pi+ Apelin− group: 50.1 ± 6.21 ug/mg vs 146.67 ± 10.02 ug/mg protein, p = 0.012) and to suppress the induction of the osteoblastic transformation genes BMP-2, osteoprotegerin (OPG) and Cbfa1. This effect was mediated by interference of the sodium-dependent phosphate cotransporter (Pit-1) expression and phosphate uptake. In vivo, decreased plasma apelin levels (adenine+ apelin− vs vehicle: 0.37 ± 0.09 ng/ml vs 0.68 ± 0.16 ng/ml, p = 0.003) and downregulation of APJ in the aorta were found in adenine-induced CKD rats with hyperphosphatemia (adenine+ apelin− vs vehicle: 6.91 ± 0.23 mmoL/L vs 2.3 ± 0.07 mmoL/L, p = 0.001) and aortic calcification. Exogenous supplementation of apelin-13 normalized the level of the apelin/APJ system and significantly ameliorated aortic calcification, as well as the suppression of Runx2, OPG and Pit-1 expression.ConclusionsApelin ameliorates VC by suppressing osteoblastic differentiation of VSMCs through downregulation of Pit-1. These results suggest apelin may have potential therapeutic value for treatment of VC in CKD.