Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate

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Abstract

Vascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are promising candidates to treat CKD-associated anemia by increasing erythropoietin synthesis. Recent evidence suggests that HIFs play a pivotal role in vascular calcification. Our study explored feasible impacts of HIF PHI on phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs) and tested whether zinc might inhibit this mineralization process. Treatment of VSMCs with PHI aggravated Pi-induced calcium deposition and Pi uptake. PHI promoted Pi-induced loss of smooth muscle cell markers (ACTA-2, MYH11, SM22α) and enhanced osteochondrogenic gene expression (Msx-2, BMP-2, Sp7) triggering osteochondrogenic phenotypic switch of VSMCs. These effects of PHI paralleled with increased pyruvate dehydrogenase kinase 4 (PDK4) expression, decreased Runx2 Ser451 phosphorylation, and reduced cell viability. Zinc inhibited Pi-induced mineralization of VSMCs in a dose-dependent manner and also attenuated the pro-calcification effect of PHI in Pi-induced mineralization. Zinc inhibited osteochondrogenic phenotypic switch of VSMCs reflected by lowering Pi uptake, decreasing the expressions of Msx-2, BMP-2, and Sp7 as well as the loss of smooth muscle cell-specific markers. Zinc preserved phosphorylation state of Runx2 Ser451, decreased PDK4 level, and restored cell viability. PHI alone reduced the expression of smooth muscle markers without inducing mineralization, which was also inhibited by zinc. In addition, we observed a significantly lower serum zinc level in CKD as well as in patients undergoing carotid endarterectomy compared to healthy individuals. Conclusion - PHI promoted the loss of smooth muscle markers and augmented Pi-induced osteochondrogenic phenotypic switch leading to VSMCs calcification. This mineralization process was attenuated by zinc. Enhanced vascular calcification is a potential risk factor during PHI therapy in CKD which necessitates the strict follow up of vascular calcification and zinc supplementation.

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Chronic Kidney Disease.

Angela Webster, Evi V Nagler, Rachael Morton … (2017)

The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m(2), or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests (urinary dipstick or blood tests), or when symptoms become severe. The best available indicator of overall kidney function is GFR, which is measured either via exogenous markers (eg, DTPA, iohexol), or estimated using equations. Presence of proteinuria is associated with increased risk of progression of CKD and death. Kidney biopsy samples can show definitive evidence of CKD, through common changes such as glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Complications include anaemia due to reduced production of erythropoietin by the kidney; reduced red blood cell survival and iron deficiency; and mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism. People with CKD are five to ten times more likely to die prematurely than they are to progress to end stage kidney disease. This increased risk of death rises exponentially as kidney function worsens and is largely attributable to death from cardiovascular disease, although cancer incidence and mortality are also increased. Health-related quality of life is substantially lower for people with CKD than for the general population, and falls as GFR declines. Interventions targeting specific symptoms, or aimed at supporting educational or lifestyle considerations, make a positive difference to people living with CKD. Inequity in access to services for this disease disproportionally affects disadvantaged populations, and health service provision to incentivise early intervention over provision of care only for advanced CKD is still evolving in many countries.

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Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

A S Levey, R. Atkins, J Coresh … (2007)

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

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KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

, (2006)

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Author and article information

Contributors

Annamária Nagy: URI : http://loop.frontiersin.org/people/635836/overview

Dávid Pethő: URI : http://loop.frontiersin.org/people/635822/overview

Tamás Gáll: URI : http://loop.frontiersin.org/people/499608/overview

Abolfazl Zarjou: URI : http://loop.frontiersin.org/people/162086/overview

Anupam Agarwal: URI : http://loop.frontiersin.org/people/495466/overview

György Balla: URI : http://loop.frontiersin.org/people/636411/overview

József Balla: URI : http://loop.frontiersin.org/people/51015/overview

Journal

Journal ID (nlm-ta): Front Physiol

Journal ID (iso-abbrev): Front Physiol

Journal ID (publisher-id): Front. Physiol.

Title: Frontiers in Physiology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-042X

Publication date (Electronic): 15 January 2020

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 1584

Affiliations

[1] ¹Department of Internal Medicine, Faculty of Medicine, University of Debrecen , Debrecen, Hungary

[2] ²Kálmán Laki Doctoral School, University of Debrecen , Debrecen, Hungary

[3] ³HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences , Debrecen, Hungary

[4] ⁴Department of Pediatrics, Faculty of Medicine, University of Debrecen , Debrecen, Hungary

[5] ⁵Department of Inorganic and Analytical Chemistry, UD Faculty of Science and Technology, University of Debrecen , Debrecen, Hungary

[6] ⁶Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham , Birmingham, AL, United States

Author notes

Edited by: Lacolley Patrick, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by: Wei Kong, Peking University, China; Julian Albarran Juarez, Aarhus University, Denmark

*Correspondence: József Balla, balla@ 123456belklinika.com

This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

Article

DOI: 10.3389/fphys.2019.01584

PMC ID: 6974455

PubMed ID: 32009983

SO-VID: 744c850e-0213-43fb-a250-ac96ea826f57

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 09 July 2019

Date accepted : 17 December 2019

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Figures: 9, Tables: 0, Equations: 0, References: 53, Pages: 15, Words: 0

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Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate

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Most cited references 43

Chronic Kidney Disease.

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

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