Regulation of the Sodium-Phosphate Cotransporter Pit-1 and its Role in Vascular Calcification

Abstract

Vascular calcification is caused by the deposition of basic calcium phosphate crystals in blood vessels, myocardium, and/or cardiac valves. Calcification decreases artery wall compliance, and arterial calcification is associated to mortality in hyperphosphatemic renal failure and diabetes mellitus. The calcification of the tunica media characterizes the arteriosclerosis observed with age, diabetes and end stage-renal disease, and it can develop independently from intima calcification. As part of the vascular calcification mechanism, vascular smooth muscle cells (VSMC) experience a transition from a contractile to an osteochondrogenic phenotype and a sequence of molecular events that are typical of endochondral ossification. The current evidence indicates a key role of increased phosphate uptake by VSMC for calcification, which supplies the substrate for hydroxyapatite formation and could trigger or potentiate VSMC transdiferentiation. The present review analyzes the sodium-phosphate cotransporter Pit-1, which is implicated in calcification. On the basis of the available data obtained in the study of vascular and osteoblastic experimental models, we discuss potential regulatory mechanisms that could lead to increased sodium-dependent phosphate uptake in vascular calcification.

Spironolactone ameliorates arterial medial calcification in uremic rats: the role of mineralocorticoid receptor signaling in vascular calcification

“…A recent experimental study showed that SPL inhibits transdifferentiation of VSMCs into osteoblast-like cells by downregulating Pit-1 and prevents VC in klotho-hypomorphic mice (39). In addition, Pit-1 silencing suppressed all the VC-related genes in the cultured VSMCs (16,39). In our study, CKD rats showed upregulation of Pit-1 and Runx2, whereas SPL attenuated these increases independently of plasma aldosterone and ANG II concentration.…”

“…Pit-1, expressed in various cells, is a sodium-P i cotransporter that regulates P i entry into cells (16). P i entry into VSMCs through Pit-1 is the first critical step in the VC cascade (14).…”

“…Another important downstream target of MR signaling in the VC process is Sgk-1, which possesses a putative MR-responsive element (16,39) and has been shown to regulate epithelial sodium channel expression in the kidney (37). Importantly, Sgk-1 was shown to activate the NF-B pathway and induce inflammation, apoptosis, and fibrosis in the heart, breast cancer cells, and glomerular mesangial cells (36, 37a, 47).…”

Association between a Novel Mutation in SLC20A2 and Familial Idiopathic Basal Ganglia Calcification

“…This is consistent with the minimal and late onset of the symptoms because no neuronal damage occurs during the early stages of IBGC. Studies on the pathogenesis of vascular calcification induced by phosphate showed that SLC20A1 has a determinant role in the mineralization of vascular cells in vitro [19], [20]. For this reason, we propose that both SLC20A1 and SLC20A2 might be involved in the pathogenesis of FIBGC.…”

Reconstituição da Anexina V em sistemas de lipossomos: associação com a fosfatase alcalina e correlação com estudos de biomineralização

“…As principais biomoléculas responsáveis pelo processo de biomineralização descritas atualmente são: (i) fosfatase alcalina, também denominada TNAP (fosfatase alcalina não específica de tecido), que apresenta atividade fosfomonohidrolítica, produzindo fosfato a partir, principalmente, de pirofosfato (PP i ) e ATP; (ii) nucleosídeo trifosfato difosfohidrolase 1 (NPP1), enzima responsável pela formação de PP i a partir de nucleosídeos fosforilados; (iii) uma fosfomonohidrolase encontrada especificamente dentro das vesículas, denominada PHOSPHO1, responsável pelo aumento da concentração de P i intravesicular acoplado à degradação de fosfolipídios, através da hidrólise de fosfocolina e fosfoetanolamina (Roberts et al, 2004); (iv) transportadores de P i PiT-1 e PiT-2 (Caverzasio et al, 1988;Montessuit et al, 1991;Palmer et al, 1997), proteínas também chamadas de cotransportadores Na + /Pi do tipo III, e originalmente identificadas como receptores retrovirais (Collins et al, 2004), atualmente estão emergindo como importantes moléculas envolvidas tanto no metabolismo de Pi ósseo quanto em processos patológicos, como calcificação induzida por hiperfosfatemia do tecido vascular e osteoartrite (Zoidis et al, 2004;Cecil et al, 2005;Li et al, 2006;Li e Giachelli, 2007;Yoshiko et al, 2007;Gonzalez et al, 2009;Mune et al, 2009;Lau et al, 2010); (v) fosfatidilserina (PS), fosfatidilcolina (PC), colesterol e (vi) Anexinas, que são uma grande família de proteínas ácidas que se ligam fortemente ao cálcio e PS (Kirsch et al, 1997;Millán, 2006;2013;Golub, 2009;Ciancaglini et al, 2010;Golub, 2011).…”