High phosphate directly affects endothelial function by downregulating annexin II

Marco, Giovana Seno Di; König, Maximilian; Stock, Christian; Wiesinger, Anne; Hillebrand, Uta; Reiermann, Stefanie; Reuter, Stefan; Amler, Susanne; Köhler, Gabriele; Buck, Friedrich; Fobker, Manfred; Kümpers, Philipp; Oberleithner, Hans; Hausberg, Martin; Lang, Detlef; Pavenstädt, Hermann; Brand, Marcus

doi:10.1038/ki.2012.300

Cited by 101 publications

(93 citation statements)

References 43 publications

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“…NO synthesis, annexin II regulation, etc.) (Lau et al 2011, Di Marco et al 2013. In acromegaly, it may be that potentially beneficial effects of GH and Klotho on endothelial function and NO synthesis are outweighed by IR and hyperphosphataemia, so that there is a net increase in cardiovascular risk.…”

Section: Gh and Klothomentioning

confidence: 99%

Growth hormone and Klotho

Schmid

Neidert

Tschopp

et al. 2013

Journal of Endocrinology

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Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.

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Section: Gh and Klothomentioning

confidence: 99%

Growth hormone and Klotho

Schmid

Neidert

Tschopp

et al. 2013

Journal of Endocrinology

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“…Some recent findings suggest that EMPs are not only markers of endothelial damage but may also be involved in ED, probably because of their protein content. 48 In an elegant study, Di Marco et al 49 recently demonstrated that high phosphate levels induces EMP shedding. After observing the large number of annexin-II positive EMPs, the researchers speculated that the induced EMP shedding decreases intracellular levels of annexin-II and thus results in impaired ECs with thrombotic, inflammatory and anti-angiogenic properties.…”

Section: Indirect Effects Of Phosphate On CV Calcification and Edmentioning

confidence: 99%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

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In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

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“…7 MPs are, therefore, associated with a prothrombotic state and may contribute to acute occlusive events in CKD. It has recently been reported that Pi can increase the generation of MPs from cultured ECs, 12 but the molecular basis of Pi's action is obscure. In this study, we test the hypothesis that hyperphosphatemia elevates intracellular Pi concentration in ECs, resulting in direct global inhibition by Pi ions of phosphoprotein phosphatases.…”

mentioning

confidence: 99%

Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells

Abbasian¹,

Burton²,

Herbert

et al. 2015

Journal of the American Society of Nephrology

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Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine-and serine/ threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1-to 1-mm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.

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High phosphate directly affects endothelial function by downregulating annexin II

Cited by 101 publications

References 43 publications

Growth hormone and Klotho

Growth hormone and Klotho

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells

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