DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease.
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ABSTRACT:
SUBMITTER: Dussold C
PROVIDER: S-EPMC6483996 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
| S-EPMC3204831 | biostudies-other
Project description:Background and objectivesHigh plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD.Design, setting, participants, & measurementsWe performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ?95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level.ResultsMedian age was 12 years (interquartile range, 8-15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38-64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P<0.01) in participants with FGF23 concentrations ?170 RU/ml compared with those with FGF23<100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR?45 ml/min per 1.73 m2, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 <100 RU/ml, 100-169 RU/ml, and ?170 RU/ml, respectively (Ptrend=0.01). When eGFR was ?45 ml/min per 1.73 m2, higher FGF23 concentrations were independently associated with LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24; P<0.05; fully adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; P<0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m2, FGF23 did not associate with LVH.ConclusionsPlasma FGF23 concentration ?170 RU/ml is an independent predictor of LVH in children with eGFR?45 ml/min per 1.73 m2.
| S-EPMC5753303 | biostudies-literature
Project description:BackgroundIn chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously.MethodsWe conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sex-matched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescence microscopy, qRT-PCR and western blotting.ResultsThe majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant.ConclusionsOur results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.
| S-EPMC6388939 | biostudies-literature
Project description:BackgroundPatients with chronic kidney disease (CKD) have a high risk of left ventricular hypertrophy (LVH). Fibroblast growth factor 23 (FGF23) and indoxyl sulfate (IS) are associated with LVH in patients with CKD, but the interactions between these molecules remain unknown. We investigated whether IS contributes to LVH associated with FGF23 in cultured cardiomyocytes and CKD mice.Methods and resultsIn cultured rat cardiac myoblast H9c2 cells incubated with IS, mRNA levels of the LVH markers atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain were significantly upregulated. Levels of mRNA of the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which regulates FGF23 O-glycosylation, and FGF23 were also upregulated in H9c2 cells. Intact FGF23 protein expression and fibroblast growth factor receptor 4 (FGFR4) phosphorylation were increased in cell lysates by IS administration. In C57BL/6J mice with heminephrectomy, IS promoted LVH, whereas the inhibition of FGFR4 significantly reduced heart weight and left ventricular wall thickness in IS-treated groups. While there was no significant difference in serum FGF23 concentrations, cardiac FGF23 protein expression was markedly increased in IS-injected mice. GALNT3, hypoxia-inducible factor 1 alpha, and FGF23 protein expression was induced in H9c2 cells by IS treatment and suppressed by the inhibition of Aryl hydrocarbon receptor which is the receptor for IS.ConclusionThis study suggests that IS increases FGF23 protein expression via an increase in GALNT3 and hypoxia-inducible factor 1 alpha expression, and activates FGF23-FGFR4 signaling in cardiomyocytes, leading to LVH.
| S-EPMC9988908 | biostudies-literature
Project description:Left ventricular hypertrophy (LVH) is a primary feature of cardiovascular complications in patients with chronic kidney disease (CKD). miRNA-30 is an important posttranscriptional regulator of LVH, but it is unknown whether miRNA-30 participates in the process of CKD-induced LVH. In the present study, we found that CKD not only resulted in LVH but also suppressed miRNA-30 expression in the myocardium. Rescue of cardiomyocyte-specific miRNA-30 attenuated LVH in CKD rats without altering CKD progression. Importantly, in vivo and in vitro knockdown of miRNA-30 in cardiomyocytes led to cardiomyocyte hypertrophy by upregulating the calcineurin signaling directly. Furthermore, CKD-related detrimental factors, such as fibroblast growth factor-23, uremic toxin, angiotensin II, and transforming growth factor-β, suppressed cardiac miRNA-30 expression, while miRNA-30 supplementation blunted cardiomyocyte hypertrophy induced by such factors. These results uncover a potentially novel mechanism of CKD-induced LVH and provide a potential therapeutic target for CKD patients with LVH.
| S-EPMC8262338 | biostudies-literature
Project description:Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy. This is especcialy the case for small non-coding microRNAs but was also, although in a smaller scale, convincingly demonstrated for other members of cellular epigenome landscape. Equally important, and clinically most relevant, the reported data indicate that epigenetic marks, particularly certain microRNA signatures, could represent useful non-invasive biomarkers that reflect the disease progression and patients prognosis for recovery after the valve replacement surgery.
| S-EPMC5627415 | biostudies-literature
Project description:BackgroundThe level of serum uric acid (SUA) has been reported to be associated with left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD). However, this association remains unclear in patients with chronic kidney disease (CKD).MethodsA total of 1025 patients with pre-dialysis CKD with preserved left ventricular systolic function were enrolled in this cross-sectional study. The LVH and LVDD were assessed using two-dimensional echocardiography and tissue Doppler imaging. The associations of LVH/LVDD with clinical and laboratory variables were investigated using univariable and multivariable logistic regression analyses.ResultsIn a multivariable analysis, the SUA level was an independent predictor of LVH (odds ratio [OR]: 1.40, 95% confidence interval [CI]: 1.31-1.50, P < 0.001). In addition, patient age, systolic blood pressure, intact parathyroid hormone levels, and left atrial volume index levels were independent predictors of LVH. The SUA level was also an independent predictor of LVDD (OR: 1.93, 95% CI: 1.53-2.43, P < 0.001). Furthermore, systolic blood pressure and left atrial volume index levels were an independent predictor of LVDD. Receiver-operating characteristic curve analysis showed that the best cutoff values of SUA levels for identifying LVH and LVDD were ≥ 7.5 mg/dL and ≥ 6.3 mg/dL, respectively.ConclusionThe SUA level was an independent predictor of LVD and LVDD in patients with CKD, suggesting that SUA could be a biomarker for LVH and LVDD.
| S-EPMC8101764 | biostudies-literature
Project description:Fibroblast growth factor 23(FGF23) is the most important biomarker and pathogenic factor in Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). In the moderate and severe stages of chronic renal failure, abnormally elevated circulating FGF23 can lead to some complications, including myocardial hypertrophy, which is positively correlated with all-cause mortality. However, the circulating FGF23 level of different hemodialysis modalities, the underlying essential regulatory factors, and potential clinical benefits remain to be elucidated. In this retrospective cohort study, 90 in-center nocturnal hemodialysis (INHD) and 90 matched conventional hemodialysis (CHD) patients were enrolled. The complete blood count, intact FGF23(iFGF23), calcium, phosphorus, PTH, and other biochemical and echocardiographic parameters of INHD and CHD patients were collected and analyzed at 1-year follow-up. The all-cause mortality was recorded during the 7-year follow-up. Furthermore, the regulatory factors of iFGF23 and its association with echocardiographic parameters and mortality were investigated by multivariate regression. The levels of iFGF23 and serum phosphate in patients undergoing INHD were significantly lower than those in patients undergoing CHD. The left ventricular volume index (LVMI) in patients with INHD was significantly attenuated and positively correlated with the drop of serum iFGF23. The INHD group had reduced all-cause mortality compared to the CHD group. Multivariate analysis showed that iFGF23 was positively correlated with serum calcium, serum phosphorus, and calcium-phosphate product. The calcium-phosphate product is an independent determining factor of serum iFGF23. Compared with the CHD group, the INHD group presented with a significantly reduced circulating iFGF23 level, which was closely associated with attenuation of left ventricular hypertrophy, but INHD reduced all-cause mortality in an FGF23 independent manner.
| S-EPMC9253468 | biostudies-literature
Project description:Cardiovascular diseases remain the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). The aim of the study was to assess the association between oxidative stress biomarkers and cardiovascular risk factors and left ventricular hypertrophy in children with CKD. Material and Methods. The studied group consisted of 65 patients aged 1.4-18.6 (mean 11.2) years with stages 1 to 5 CKD. Serum oxidized low-density lipoprotein (oxLDL), protein carbonyl group, creatinine, cystatin C, albumin, lipids, high-sensitivity C-reactive protein, intercellular adhesion molecule-1, insulin, plasma renin activity, and aldosterone levels were measured. Patients were divided into groups depending on CKD stage. Anthropometric measurements, ambulatory blood pressure (BP) measurements, and echocardiography with left ventricular mass (LVM) calculation were performed. Results. Serum oxLDL strongly correlated with creatinine (R = 0.246; p = 0.048), cystatin C (R = 0.346; p = 0.006), total cholesterol (R = 0.500; p < 0.001), triglycerides (R = 0.524; p < 0.001), low-density lipoprotein concentrations (R = 0.456; p < 0.001), and 24 hour BP values of systolic (R = 0.492; p = 0.002), diastolic (R = 0.515; p < 0.001), and mean arterial pressure (R = 0.537; p < 0.001). A significant correlation between oxLDL levels and LVM z-scores (R = 0.299; p = 0.016) was found. Conclusions. Hypertension and dyslipidemia correlated with lipid oxidation in children with CKD. oxLDLs seem to be valuable markers of oxidative stress in CKD patients, correlating with left ventricular hypertrophy.
| S-EPMC4739446 | biostudies-literature
Project description:ObjectiveVolume overload is a frequent feature related to left ventricular hypertrophy (LVH) in dialysis patients, but its influence on patients with chronic kidney disease (CKD) not on dialysis has not been accurately uncovered. This article was to examine the relationship between overhydration (OH) and LVH in patients with CKD not yet on dialysis.MethodsA total of 302 patients with CKD stages 1-4 were included. Participants were divided into different subgroups according to occurring LVH or not, and OH tertiles. Clinical and laboratory parameters were compared among groups. Spearman correlation analyses were adopted to explore the relationships of echocardiographic findings with the clinical and laboratory characteristics. Binary logistic regression models were performed to estimate the odds ratios (ORs) for the associations between OH and LVH. Restricted cubic splines were implemented to assess the possible non-linear relationship between OH and LVH. LVH was defined as left ventricular mass index (LVMI) >115 g/m2 in men and >95 g/m2 in women.ResultsOf the enrolled patients with CKD, the mean age was 45.03 ± 15.14 years old, 165 (54.6%) cases were men, and 65 (21.5%) cases had LVH. Spearman correlation analyses revealed that OH was positively correlated with LVMI (r = 0.263, P < 0.001). After adjustment for age, gender, diabetes, body mass index (BMI), systolic blood pressure (SBP), hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), and logarithmic transformation of urinary sodium and urinary protein, multivariate logistic regression analyses demonstrated that both the middle and highest tertile of OH was associated with increased odds of LVH [OR: 3.082 (1.170-8.114), P = 0.023; OR: 4.481 (1.332-15.078), P = 0.015, respectively], in comparison to the lowest tierce. Restricted cubic spline analyses were employed to investigate the relationship between OH and LVH, which unfolded a significant non-linear association (P for non-linear = 0.0363). Furthermore, patients were divided into two groups according to CKD stages. The multivariate logistic regression analyses uncovered that increased odds of LVH were observed in the middle and the highest tertile of OH [OR: 3.908 (0.975-15.670), P = 0.054; OR: 6.347 (1.257-32.054), P = 0.025, respectively] in patients with stages 1-2.ConclusionThese findings suggest that a higher level of OH was associated with a higher occurrence of LVH in patients with CKD not on dialysis, especially in patients with CKD stages 1-2.
| S-EPMC8916701 | biostudies-literature