Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification

Mokas, Sophie; Lariviere, Richard W.; Lamalice, Laurent; Gobeil, Stéphane; Cornfield, David N.; Agharazii, Mohsen; Richard, Darren E.

doi:10.1016/j.kint.2016.05.020

Cited by 115 publications

(126 citation statements)

References 71 publications

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“…A recent study in animal models investigated the role of hypoxia and HIF‐1 signaling in the development of vascular calcifications. The study suggested that HIF‐PHIs might enhance phosphate‐induced vascular smooth muscle cell calcification in CKD or ESRD patients with poorly controlled mineral bone metabolism . A molecular link also exists between HIF and FGF23 signaling, which may negatively impact cardiovascular risk in HIF‐PHI‐treated CKD patients .…”

Section: Hif‐prolyl Hydroxylases As Drug Targets In Renal Anemiamentioning

confidence: 98%

HIF‐prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

Haase

2017

Hemodialysis International

135

114

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A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.

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Section: Hif‐prolyl Hydroxylases As Drug Targets In Renal Anemiamentioning

confidence: 98%

HIF‐prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

Haase

2017

Hemodialysis International

135

114

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“…HIF-1 has been reported to play a crucial role in vascular smooth muscle cell (VSMC) calcification [127]. During the progression of CKD, VSMC calcification and osteogenic trans-differentiation are significantly promoted by hypoxic condition.…”

Section: Hif In Ckd-associated Syndromesmentioning

confidence: 99%

“…Meanwhile, HIF-1 activators can further promote inorganic phosphate induced calcification. Together, hypoxia can synergize with elevated inorganic phosphate through HIF-1 induction to enhance VSMC osteogenic transdifferentiation [127]. Furthermore, Bone Gla Protein (BGP), a marker for bone formation which is induced in calcified vasculatures, may also promote HIF-1α expression and further stimulate the calcification [128].…”

Section: Hif In Ckd-associated Syndromesmentioning

confidence: 99%

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

Liu¹,

Wei²,

Guo³

et al. 2017

IJMS

107

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The pathogenesis of chronic kidney disease (CKD) is complex and apparently multifactorial. Hypoxia or decrease in oxygen supply in kidney tissues has been implicated in CKD. Hypoxia inducible factors (HIF) are a small family of transcription factors that are mainly responsive to hypoxia and mediate hypoxic response. HIF plays a critical role in renal fibrosis during CKD through the modulation of gene transcription, crosstalk with multiple signaling pathways, epithelial-mesenchymal transition, and epigenetic regulation. Moreover, HIF also contributes to the development of various pathological conditions associated with CKD, such as anemia, inflammation, aberrant angiogenesis, and vascular calcification. Treatments targeting HIF and related signaling pathways for CKD therapy are being developed with promising clinical benefits, especially for anemia. This review presents an updated analysis of hypoxia response, HIF, and their associated signaling network involved in the pathogenesis of CKD.

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“…Phosphate loading induces the expression of hypoxia‐inducible factor‐1α (HIF‐1α) in smooth muscle cells (SMCs) . This transcription factor is reported to be responsible for the calcification of SMCs by phosphate loading.…”

Section: Potential Solutions For Vascular Calcification In the Futurementioning

confidence: 99%

Mineral and bone disorders in conventional hemodialysis: Challenges and solutions

Hamano

2018

Seminars in Dialysis

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Despite the advent of cinacalcet and noncalcium-containing phosphate binders, controlling the progression of vascular calcification (VC) is still challenging. Recent reports demonstrate that carbamylation driven by high urea concentration aggravates VC, suggesting the importance of adequate dialysis in retarding its progression. Theoretically, other promising measures include the use of iron-based phosphate binders, vitamin K, and magnesium supplements, which should be investigated in future randomized controlled trials (RCTs), ideally with hard outcomes. While incidence of hip fracture in patients on dialysis is decreasing in the United States and Japan (possibly owing to better control of PTH levels by cinacalcet) it remains much higher than that in the general population. Many drugs used in the treatment of osteoporosis, including bisphosphonate, raloxifene, denosumab, and teriparatide can, under specific conditions, increase bone mineral density (BMD), which is associated with a lower fracture rate. However, the efficacy of these drugs in reducing the fracture rate remains to be proven in hemodialysis (HD) patients, given their adverse effects such as severe hypocalcemia and resultant worsening of secondary hyperparathyroidism. Some clinical studies have shown that cinacalcet, lanthanum carbonate, and sevelamer reduce mortality in elderly patients on HD, suggesting the benefits of reducing PTH and serum phosphate levels. However, the target ranges of PTH and phosphate levels are based solely on observational studies. This is also the case when treating low PTH levels by decreasing vitamin D or calcium load. RCTs with hard clinical endpoints comparing different targets are necessary in the future.

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Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification

Cited by 115 publications

References 71 publications

HIF‐prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

HIF‐prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

Mineral and bone disorders in conventional hemodialysis: Challenges and solutions

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