Abstract
Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs). High phosphate concentrations up-regulated aldosterone synthase (CYP11B2) expression in HAoSMCs. Silencing and deficiency of CYP11B2 in VSMCs ameliorated phosphate-induced osteogenic reprogramming and calcification. Phosphate treatment was followed by nuclear export of APEX1, a CYP11B2 transcriptional repressor. APEX1 silencing up-regulated CYP11B2 expression and stimulated osteo-/chondrogenic transformation. APEX1 overexpression blunted the phosphate-induced osteo-/chondrogenic transformation and calcification of HAoSMCs. Cyp11b2 expression was higher in aortic tissue of hyperphosphatemic klotho-hypomorphic (kl/kl) mice than in wild-type mice. In adrenalectomized kl/kl mice, spironolactone treatment still significantly ameliorated aortic osteoinductive reprogramming. Our findings suggest that VSMCs express aldosterone synthase, which is up-regulated by phosphate-induced disruption of APEX1-dependent gene suppression. Vascular CYP11B2 may contribute to stimulation of VSMCs osteo-/chondrogenic transformation during hyperphosphatemia.
Highlights
Phosphate concentration, which predisposes to calcification of the medial artery layer[3]
PiT1, CBFA1 and ALPL mRNA levels were up-regulated by phosphate in negative control silenced human aortic smooth muscle cells (HAoSMCs), but not in HAoSMCs silenced with mineralocorticoid receptor (MR) siRNA (Fig. 1d)
CYP11B2 expression was up-regulated by elevated extracellular phosphate concentrations and CYP11B2 was required for the triggering of osteo-/chondrogenic reprogramming of vascular smooth muscle cells (VSMCs) following phosphate treatment
Summary
Phosphate concentration, which predisposes to calcification of the medial artery layer[3]. In response to elevated extracellular phosphate concentrations, VSMCs differentiate and undergo osteo-/chondrogenic reprogramming[7]. This reprogramming involves enhanced expression of type III sodium-dependent phosphate transporter PiT1 (SLC20A1)[8] and is characterized by expression of osteoblastic transcription factors Msh homeobox 2 (MSX2) and core-binding factor alpha 1 (CBFA1, encoded by the runt-related transcription factor 2; RUNX2 gene)[9, 10]. The markers of vascular osteo-/chondrogenic transformation are up-regulated before the onset of vascular calcification[12]. Indicators of VSMC osteo-/chondrogenic transformation are observed in vessels from human CKD patients[13]. The present study explored the possibility that vascular CYP11B2 may participate in the induction of osteo-/chondrogenic transformation of VSMCs
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