Dataset Information

Elevated serum magnesium lowers calcification propensity in Memo1-deficient mice.

ABSTRACT: MEdiator of cell MOtility1 (MEMO1) is a ubiquitously expressed redox protein involved in extracellular ligand-induced cell signaling. We previously reported that inducible whole-body Memo1 KO (cKO) mice displayed a syndrome of premature aging and disturbed mineral metabolism partially recapitulating the phenotype observed in Klotho or Fgf23-deficient mouse models. Here, we aimed at delineating the contribution of systemic mineral load on the Memo1 cKO mouse phenotype. We attempted to rescue the Memo1 cKO phenotype by depleting phosphate or vitamin D from the diet, but did not observe any effect on survival. However, we noticed that, by contrast to Klotho or Fgf23-deficient mouse models, Memo1 cKO mice did not present any soft-tissue calcifications and displayed even a decreased serum calcification propensity. We identified higher serum magnesium levels as the main cause of protection against calcifications. Expression of genes encoding intestinal and renal magnesium channels and the regulator epidermal growth factor were increased in Memo1 cKO. In order to check whether magnesium reabsorption in the kidney alone was driving the higher magnesemia, we generated a kidney-specific Memo1 KO (kKO) mouse model. Memo1 kKO mice also displayed higher magnesemia and increased renal magnesium channel gene expression. Collectively, these data identify MEMO1 as a novel regulator of magnesium homeostasis and systemic calcification propensity, by regulating expression of the main magnesium channels.

SUBMITTER: Moor MB

PROVIDER: S-EPMC7380890 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Elevated serum magnesium lowers calcification propensity in Memo1-deficient mice.

Moor Matthias B MB Ramakrishnan Suresh K SK Legrand Finola F Bachtler Matthias M Koesters Robert R Hynes Nancy E NE Pasch Andreas A Bonny Olivier O

PloS one 20200724 7

MEdiator of cell MOtility1 (MEMO1) is a ubiquitously expressed redox protein involved in extracellular ligand-induced cell signaling. We previously reported that inducible whole-body Memo1 KO (cKO) mice displayed a syndrome of premature aging and disturbed mineral metabolism partially recapitulating the phenotype observed in Klotho or Fgf23-deficient mouse models. Here, we aimed at delineating the contribution of systemic mineral load on the Memo1 cKO mouse phenotype. We attempted to rescue the ...[more]

PMID: 32706793

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Project description:BACKGROUND AND OBJECTIVES:Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. RESULTS:The mean T50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T50, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T50, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T50, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T50, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. CONCLUSIONS:Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.

Project description:Vascular calcification contributes to cardiovascular morbidity and mortality. A recently developed serum calcification propensity assay is based on the half-transformation time (T50) from primary calciprotein particles (CPPs) to secondary CPPs, reflecting the serum's endogenous capacity to prevent calcium phosphate precipitation. We sought to identify and review the results of all published studies since the development of the T50-test by Pasch et al. in 2012 (whether performed in vitro, in animals or in the clinic) of serum calcification propensity. To this end, we searched PubMed, Elsevier EMBASE, the Cochrane Library and Google Scholar databases from 2012 onwards. At the end of the selection process, 57 studies were analyzed with regard to the study design, sample size, characteristics of the study population, the intervention and the main results concerning T50. In patients with primary aldosteronism, T50 is associated with the extent of vascular calcification in the abdominal aorta. In chronic kidney disease (CKD), T50 is associated with the severity and progression of coronary artery calcification. T50 is also associated with cardiovascular events and all-cause mortality in CKD patients, patients on dialysis and kidney transplant recipients and with cardiovascular mortality in patients on dialysis, kidney transplant recipients, patients with ischemic heart failure and reduced ejection fraction, and in the general population. Switching from acetate-acidified dialysate to citrate-acidified dialysate led to a longer T50, as did a higher dialysate magnesium concentration. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with a lower serum calcification propensity. Serum calcification propensity is an overall marker of calcification associated with hard outcomes but is currently used in research projects only. This assay might be a valuable tool for screening serum calcification propensity in at-risk populations (such as CKD patients and hemodialyzed patients) and, in particular, for monitoring changes over time in T50.

Project description:BACKGROUND AND OBJECTIVES:Serum calcification propensity is a novel functional test that quantifies the functionality of the humeral system of calcification control. Serum calcification propensity is measured by T50, the time taken to convert from primary to secondary calciprotein particle in the serum. Lower T50 represents higher calcification propensity and is associated with higher risk of cardiovascular events and death in patients with ESKD. Increasing magnesium in serum increases T50, but so far, no clinical trials have investigated whether increasing serum magnesium increases serum calcification propensity in subjects with ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We conducted a single-center, randomized, double-blinded, parallel group, controlled clinical trial, in which we examined the effect of increasing dialysate magnesium from 1.0 to 2.0 mEq/L for 28 days compared with maintaining dialysate magnesium at 1.0 mEq/L on T50 in subjects undergoing hemodialysis for ESKD. The primary end point was the value of T50 at the end of the intervention. RESULTS:Fifty-nine subjects were enrolled in the trial, and of these, 57 completed the intervention and were analyzed for the primary outcome. In the standard dialysate magnesium group, T50 was 233±81 minutes (mean±SD) at baseline (mean of days -7 and 0) and 229±93 minutes at follow-up (mean of days 21 and 28), whereas in the high dialysate magnesium group, T50 was 247±69 minutes at baseline and 302±66 minutes at follow-up. The difference in T50 between the two groups at follow-up (primary analysis) was 73 minutes (between-group difference; 95% confidence interval, 30 to 116; P<0.001), and the between-group difference in serum magnesium was 0.88 mg/dl (95% confidence interval, 0.66 to 1.10; P=0.001). CONCLUSIONS:Increasing dialysate magnesium increases T50 and hence, decreases calcification propensity in subjects undergoing maintenance hemodialysis. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_21_CJASNPodcast_18_9_B.mp3.

Project description:RATIONALE & OBJECTIVE:Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. PREDICTORS:Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. OUTCOMES:CAC prevalence, severity, incidence, and progression. ANALYTICAL APPROACH:Multivariable-adjusted generalized linear models. RESULTS:At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. LIMITATIONS:Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. CONCLUSIONS:Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

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Elevated serum magnesium lowers calcification propensity in Memo1-deficient mice.

Publications

Elevated serum magnesium lowers calcification propensity in Memo1-deficient mice.

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