Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation

Troyano, Nuria; Nogal, María del; Mora, Inés; Diaz-Naves, Manuel; Lopez-Carrillo, Natalia; Sosa, Patricia; Rodríguez‐Puyol, Diego; Olmos, Gemma; Ruiz-Torres, María Piedad

doi:10.1016/j.mad.2015.10.001

Cited by 17 publications

(25 citation statements)

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“…Serum phosphate levels inversely correlate with the lifespan of diverse species [ 37 ] and hyperphosphatemia has been linked with premature aging phenotype in Klotho deficient mice and in FGF23 KO mice [ 19 , 20 ]. In vitro studies have demonstrated that the increase in extracellular phosphate concentration modifies the behaviour of cultured cells by inducing osteogenic and osteoclastic differentiation or cellular senescence in smooth muscle cells [ 21 , 17 ]. It is the first time that the potential role of hyperphosphatemia in modifying myoblast cell cycle has been shown.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, C 2 C 12 cells have been widely used in cellular senescence related studies [ 39 ]. C 2 C 12 cells were exposed to high extracellular phosphate concentration by adding the phosphate donor BGP, as previously described [ 17 , 40 ]. To assess whether phosphate entered the myoblast to perform its effect, we used a specific inhibitor of the Na-Pi cotransporter termed PFA [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cellular senescence is induced in different cellular types by changes in several environmental and systemic factors. Among others, hiperosmolarity, high glucose [ 15 ], glycated albumin [ 16 ] and hyperphosphatemia [ 17 ] have been described as inductors of cellular senescence. Recent studies have analyzed the role of elevated serum phosphate concentration in aging-related pathologies [ 18 ].…”

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confidence: 99%

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Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia

et al. 2018

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In mammalians, advancing age is associated with sarcopenia, the progressive and involuntary loss of muscle mass and strength. Hyperphosphatemia is an aging-related condition involved in several pathologies. The aim of this work was to assess whether hyperphosphatemia plays a role in the age-related loss of mass muscle and strength by inducing cellular senescence in murine myoblasts and to explore the intracellular mechanism involved in this effect. Cultured mouse C2C12 cells were treated with 10 mM beta-glycerophosphate (BGP] at different periods of time to induce hyperphosphatemia. BGP promoted cellular senescence after 24 h of treatment, assessed by the increased expression of p53, acetylated-p53 and p21 and senescence associated β-galactosidase activity. In parallel, BGP increased ILK expression and activity, followed by mTOR activation and autophagy reduction. Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia. BGP also reduced the proliferative capacity of cultured myoblasts. Old mice (24-months-old] presented higher serum phosphate concentration, lower forelimb strength, higher expression of p53 and ILK and less autophagy in vastus muscle than young mice (5-months-old]. In conclusion, we propose that hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression, reducing their proliferative capacity, which could be a mechanism involved in the development of sarcopenia, since old mice showed loss of muscular strength correlated with high serum phosphate concentration and increased levels of ILK and p53.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia

et al. 2018

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“…In accordance with these observations, unstable, mature plaques show clear evidence of VSMC senescence [ 119 , 120 ], and restenosed neointimas also contain senescent VSMCs [ 121 ]. It is noteworthy that vascular tissues from CKD animals contain elevated levels of SaβG [ 122 , 123 ], suggesting that uremia promotes CVD by increasing VSMC senescence.…”

Section: The Impact Of Uremic Toxins On Vsmc Functionmentioning

confidence: 99%

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

Hénaut

Mary

Chillon

et al. 2018

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Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling.

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“…Senescence can be promoted by the replicative life of cells, due to the progressive telomere shortening (Collado et al ., ) or prematurely in response to stressful stimuli, which result in DNA damage (Wang et al ., ) or oncogene activation (Serrano et al ., ). Recent studies from our group have demonstrated that hyperphosphatemia could be one of these stressful stimuli, as it induced cellular senescence in human aortic smooth muscle cells through the activation of IGF‐1 receptor and integrin‐linked kinase overexpression (Troyano et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

et al. 2017

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SummaryHyperphosphatemia is related to some pathologies, affecting vascular cell behavior. This work analyzes whether high concentration of extracellular phosphate induces endothelial senescence through up‐regulation of endothelin‐1 (ET‐1), exploring the mechanisms involved. The phosphate donor β‐glycerophosphate (BGP) in human endothelial cells increased ET‐1 production, endothelin‐converting enzyme‐1 (ECE‐1) protein, and mRNA expression, which depend on the AP‐1 activation through ROS production. In parallel, BGP also induced endothelial senescence by increasing p16 expression and the senescence‐associated β‐galactosidase (SA‐ß‐GAL) activity. ET‐1 itself was able to induce endothelial senescence, increasing p16 expression and SA‐ß‐GAL activity. In addition, senescence induced by BGP was blocked when different ET‐1 system antagonists were used. BGP increased ROS production at short times, and the presence of antioxidants prevented the effect of BGP on AP1 activation, ECE‐1 expression, and endothelial senescence. These findings were confirmed in vivo with two animal models in which phosphate serum levels were increased: seven/eight nephrectomized rats as chronic kidney disease models fed on a high phosphate diet and aged mice. Both models showed hyperphosphatemia, higher levels of ET‐1, and up‐regulation in aortic ECE‐1, suggesting a direct relationship between hyperphosphatemia and ET‐1. Present results point to a new and relevant role of hyperphosphatemia on the regulation of ET‐1 system and senescence induction at endothelial level, both in endothelial cells and aorta from two animal models. The mechanism involved showed a higher ROS production, which probably activates AP‐1 transcription factor and, as a result, ECE‐1 expression, increasing ET‐1 synthesis, which in consequence induces endothelial senescence.

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Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation

Cited by 17 publications

References 59 publications

Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia

Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

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