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Competitive endogenous RNAs (ceRNA) theory has been proved in numerous biological processes. Nevertheless, there is a lack of research applying the ceRNA theory to the study of vascular calcification (VC) in chronic kidney diseases (CKD). In the present study, a ceRNA network was constructed after conducting transcriptome sequencing of differentially expressed genes, followed by experimental validation to identify a new target for the diagnosis and treatment of vascular calcification. Total RNA was extracted from ß-glycerophosphate (ß-GP) cultured vascular smooth muscle cells (VSMCs) on Day 7. Illumina HiSeq platform was utilized to build sequencing libraries. GO and KEGG analysis was conducted to identify the function of the differentially expressed genes. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. A ceRNA network was established based on TargetScan, miRDB, miRWALK, and miRanda database. Western blot and qRT-PCR were used to explore the expression level of protein and RNA, respectively. The direct binding sites were confirmed by dual-luciferase reporter assay. In total, 647 differentially expressed lncRNAs and 289 differentially expressed mRNAs were identified (|log2FC| ≥ 1, p < .05). The function of differentially expressed mRNAs was mainly enriched in negative regulation of osteoblast differentiation, regulation of RNA metabolic process, and other typical pathways. The ceRNA network was generated with a total of 107 interaction pairs. The lncRNA Prrc2c/miR-145-5p/Smad3 axis was considered a potential regulatory pathway within the ceRNA network. The regulatory relationship and targets of this ceRNA axis were validated via in vitro experiments. For the first time, we found that lncRNA Prrc2c was highly expressed and promoted calcification of VSMCs. Luciferase reporter assay showed that lncRNA Prrc2c could bind miR-145-5p at site 1755-1761. Similarly, luciferase reporter assay showed that miR-145-5p inhibited Smad3 expression by binding to its 3'UTR. Our findings provide a comprehensive examination of the ceRNA networks in vascular smooth muscle cells (VSMCs) treated with high phosphorate. Specifically, we have identified the role of lncRNA Prrc2c in promoting VSMC calcification through the miR-145-5p/Smad3 axis.
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Redes Reguladoras de Genes , MicroRNAs , Músculo Liso Vascular , RNA Longo não Codificante , Calcificação Vascular , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Mapas de Interação de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Smad3/metabolismo , Proteína Smad3/genética , Células Cultivadas , Regulação da Expressão Gênica , Transcriptoma , Glicerofosfatos/metabolismo , RNA Endógeno CompetitivoRESUMO
BACKGROUND: Up to now, there is no unequivocal intervention to mitigate vascular calcification (VC) in patients with hemodialysis. This network meta-analysis aimed to systematically evaluate the clinical efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet in treating vascular calcification. METHODS: A comprehensive study search was performed using PubMed, Web of Science, the Cochrane Library, EMBASE and China National Knowledge Internet (CNKI) to collect randomized controlled trials (RCTs) of sodium thiosulfate, bisphosphonates, and cinacalcet for vascular calcification among hemodialysis patients. Then, network meta-analysis was conducted using Stata 17.0 software. RESULTS: In total, eleven RCTs including 1083 patients were qualified for this meta-analysis. We found that cinacalcet (SMD - 0.59; 95% CI [-0.95, -0.24]) had significant benefit on vascular calcification compared with conventional therapy, while sodium thiosulfate or bisphosphonates did not show such efficiency. Furthermore, as for ranking the efficacy assessment, cinacalcet possessed the highest surface under the cumulative ranking curve (SUCRA) value (88.5%) of lessening vascular calcification and was superior to sodium thiosulfate (50.4%) and bisphosphonates (55.4%). Thus, above results suggested that cinacalcet might be the most promising drug for vascular calcification treatment in hemodialysis patients. Mechanistically, our findings illustrated that cinacalcet reduced serum calcium (SMD - 1.20; 95% CI [-2.08, - 0.33]) and showed the tendency in maintaining the balance of intact Parathyroid Hormone (iPTH) level. CONCLUSIONS: This network meta-analysis indicated that cinacalcet appear to be more effective than sodium thiosulfate and bisphosphonates in mitigating vascular calcification through decreasing serum calcium and iPTH. And cinacalcet might be a reasonable option for hemodialysis patients with VC in clinical practice. SYSTEMATIC REVIEW REGISTRATION: [ http://www.crd.york.ac.uk/PROSPERO ], identifier [CRD42022379965].
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Difosfonatos , Tiossulfatos , Calcificação Vascular , Humanos , Difosfonatos/uso terapêutico , Cinacalcete/uso terapêutico , Metanálise em Rede , Cálcio , Calcificação Vascular/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: The objective of this study was to investigate the relationship between vascular calcification, serum lncRNA H19, and Runt-Related Transcription Factor 2 mRNA expression in patients with uremia. Methods: This study is a retrospective study which recruited 146 patients with uremia on dialysis from December 2021 to November 2022. Participants were divided into the VC and non-VC groups based on their chest X-ray calcification ratings. General and clinical data were collected from all patients. Serum H19, Runx2 mRNA, mineral bone disease effectors, and other blood markers were tested. Univariate analysis was performed to compare the changes in each clinical index between these two groups of patients. A multi-factor logistic regression analysis of risk factors for VC was performed. Receiver operating characteristics analyzed the H19 and Runx2 for their diagnostic values for VC. Pearson's test was used to analyze the correlation between the H19 and Runx2 expression and the factors influencing VC. Results: Patients in the VC group had significantly higher creatinine, serum phosphorus, calcium, BMP-2, FGF-23, OPG, and iPTH levels than those in the non-VC group (P < .05), while their albumin levels were significantly lower than those in the non-VC group (P < .05). The expression of H19 and Runx2 mRNA was significantly upregulated in the serum of VC patients (P < .05). H19 was significantly positively correlated with creatinine, serum phosphorus, calcium, BMP-2, OPG, and iPTH (P < .05). Runx2 mRNA was significantly positively correlated with creatinine, FGF-23, and iPTH (P < .05 ), while there was no significant correlation with other factors(P > .05). Albumin, BMP-2, iPTH, H19, and Runx2 were independent correlative-factors of uremic VC. In addition, the combined H19 and Runx2 test (AUC=0.850; 95% CI: 0.781-0.903) had good diagnostic values for the development of VC. Conclusion: Serum H19 and Runx2 levels are significantly associated with VC-related factors and are independent risk factors for uremic VC, and their levels contribute to the diagnosis of uremic VC.
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AIMS: This study aimed to investigate the efficacy and safety of sacubitril/valsartan in abnormal renal function (eGFR < 60 ml/min/1.73m2) patients combined with heart failure based on randomized controlled trials (RCTs) and observational studies. METHODS: The Embase, PubMed and the Cochrane Library were searched for relevant studies from inception to December 2023. Dichotomous variables were described as event counts with the odds ratio (OR) and 95% confidence interval (CI) values. Continuous variables were expressed as mean standard deviation (SD) with 95% CIs. RESULTS: A total of 6 RCTs and 8 observational studies were included, involving 17335 eGFR below 60 ml/min/1.73m2 patients combined with heart failure. In terms of efficacy, we analyzed the incidence of cardiovascular events and found that sacubitril/valsartan significantly reduced the risk of cardiovascular death or heart failure hospitalization in chronic kidney disease (CKD) stages 3-5 patients with heart failure (OR: 0.65, 95%CI: 0.54-0.78). Moreover, sacubitril/valsartan prevented the serum creatinine elevation (OR: 0.81, 95%CI: 0.68-0.95), the eGFR decline (OR: 0.83, 95% CI: 0.73-0.95) and the development of end-stage renal disease in this population (OR:0.73, 95%CI:0.60-0.89). As for safety outcomes, we did not find that the rate of hyperkalemia (OR:1.31, 95%CI:0.79-2.17) and hypotension (OR:1.57, 95%CI:0.94-2.62) were increased in sacubitril/valsartan group among CKD stages 3-5 patients with heart failure. CONCLUSIONS: Our meta-analysis proves that sacubitril/valsartan has a favorable effect on cardiac function without obvious risk of adverse events in abnormal renal function patients combined with heart failure, indicating that sacubitril/valsartan has the potential to become perspective treatment for these patients.
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Aminobutiratos , Compostos de Bifenilo , Combinação de Medicamentos , Insuficiência Cardíaca , Tetrazóis , Valsartana , Humanos , Aminobutiratos/uso terapêutico , Aminobutiratos/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Tetrazóis/uso terapêutico , Tetrazóis/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/efeitos adversos , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Creatinina/sangueRESUMO
BACKGROUND: Osteoblast phenotypic transition in vascular smooth muscle cells (VSMCs) has been unveiled as a common cause of vascular calcification (VC). Krüppel-Associated Box (KRAB)-Associated Protein 1(KAP1) is a transcriptional corepressor that modulates various intracellular pathological processes from gene expression to DNA repair to signal transduction. However, the function and mechanism of KAP1 on the osteoblastic differentiation of VSMCs have not been evaluated yet. METHODS AND RESULTS: We demonstrate that the expression of KAP1 in VSMCs is significantly enhanced in vivo and in vitro calcification models. Downregulating the expression of KAP1 suppresses the osteoblast phenotypic transition of VSMCs, which is indicated by a decrease in the expression of osteoblast marker collagenase type I (COL I) and an increase in the expression of VSMC marker α-smooth muscle actin (α-SMA). Conversely, exogenous overexpression of KAP1 could promote osteoblast phenotypic transition of VSMCs. Moreover, KAP1 upregulated the expression of RUNX family transcription factor 2 (Runx2), an inducer of osteoblast that positively regulates many osteoblast-related genes, such as COL I. Evaluation of the potential mechanism demonstrated that KAP1 promoted osteoblast phenotypic transition of VSMCs by activating the extracellular regulated protein kinases (ERK) signaling pathway, which could activate Runx2. In support of this finding, KAP1-induced cell osteoblast phenotypic transition is abolished by treatment with PD0325901, a specific ERK inhibitor. CONCLUSIONS: The present study suggested that KAP1 participated in the osteoblast differentiation of VSMCs via the ERK/Runx2 cascade and served as a potential diagnostics and therapeutics target for vascular calcification.
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Osteogênese , Calcificação Vascular , Humanos , Diferenciação Celular , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteogênese/genética , Transdução de Sinais , Calcificação Vascular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
OBJECTIVES: This study aimed to analyze the possible causes of changes in cardiac function and investigate the feasibility of clinical assessment of gastrointestinal cancer in patients with or without acute kidney injury (AKI) assessed using a non-invasive impedance cardiography (ICG, Bioz. Cardio Dynamics, USA) to identify independent risk factors. METHODS: Patients admitted to the Fourth Hospital of Hebei Medical University, China, between May 1, 2019, and February 15, 2022, were included in this study. A total of 51 patients with gastrointestinal cancer (31 men and 20 women, mean age 61.1 ± 10.9 years) with or without AKI were evaluated for ICG. A total of 19 patients underwent ultrasound cardiography (UCG) and ICG evaluations. RESULT: There was a significant positive correlation between cardiac output (CO), cardiac index (CI), stroke volume (SV), left cardiac work index (LCWI), and ejection fraction (EF) measured using UCG and ICG. The relationship was observed between COICG and COUCG (r = 0.707, P = 0.001), CIICG and CIUCG (r = 0.718, P = 0.001), SVICG and SVUCG (r = 0.837, P < 0.001), and LCWIICG and EFUCG (r = 0.540, P = 0.017). Cardiac function parameters measured using ICG were statistically different between patients with gastrointestinal cancer with or without AKI (P ≤ 0.05). Multivariate analysis revealed that AKI independently affects cardiac function in patients with gastrointestinal cancer. CONCLUSIONS: UCG and ICG methods are significantly associated with cardiac function in patients with or without AKI, and patients with gastrointestinal cancer with AKI are worse than those without AKI. AKI is an independent risk factor for cardiac function in patients with gastrointestinal cancer.
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Injúria Renal Aguda , Neoplasias , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Cardiografia de Impedância/métodos , Estudos de Casos e Controles , Débito Cardíaco , Volume Sistólico , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologiaRESUMO
Previous studies have shown that the apoptosis of vascular smooth muscle cells (VSMCs) underlies the mechanism of pathological calcification in patients with chronic kidney disease (CKD). SET domain-containing protein 8 (SET8) is an efficient protein that modulates apoptosis in hepatocellular carcinoma cells, esophageal squamous cells, and neuronal cells by regulating pathological processes, such as cell cycle progression and transcription regulation. However, whether SET8 is involved in high phosphorus-induced vascular calcification by mediating apoptosis remains unclear. Here, we report that SET8 is located both in the nucleus and cytoplasm and is significantly downregulated in calcification models. SET8 deficiency promoted apoptosis of VSMCs, as indicated by the increased Bax/Bcl-2 and cleaved caspase-3/total caspase-3 ratios. Mechanistically, the PI3K/Akt pathway was mediated by SET8, and inhibition of the PI3K/Akt signaling pathway by administering LY294002 or transfecting the Akt phosphorylation-inactivated mutation plasmid increased apoptosis and calcification. Akt phosphorylation constitutively activated mutations can reduce the apoptosis and calcification of VSMCs. Furthermore, exogenous overexpression of SET8 reversed the effect of PI3K/Akt inhibition on VSMC apoptosis and calcification. In summary, our research suggests that SET8 overexpression ameliorates high phosphorus-induced calcification of VSMCs by activating PI3K/Akt mediated anti-apoptotic effects.
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Histona-Lisina N-Metiltransferase/metabolismo , Fosfatidilinositol 3-Quinases , Calcificação Vascular , Apoptose , Células Cultivadas , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
BACKGROUND: The purpose of this study was to observe the impact of an internet-based management system on the incidence of intradialytic hypotension (IDH) and muscle cramps in hemodialysis patients. METHODS: The patients, who underwent maintenance hemodialysis in the center from January 2018 to June 2020, were recruited and divided into the pre-intervention group (before operation of the internet-based hemodialysis management system, from January 2018 to December 2018) and intervention group (after operation of the system, from June 2019 to June 2020). The clinical outcomes were compared between groups. RESULTS: The compound endpoint of >1 IDH or muscle cramps happened in 182 patients (61.7%) in the pre-intervention group and 99 participants (30.8%) in the intervention group (relative risk [RR] = 0.50 [95% confidence interval [CI], 0.42; 0.60]). IDH occurred in 122 patients (1-5 episodes in 47 patients, 6-10 episodes in 25 patients, and >10 episodes in 50 patients) and 33 patients (30 patients had 1-5 episodes and 3 patients had 6-10 episodes) before and after execution of the internet-based management system, respectively (RR = 0.25 [95% CI, 0.18; 0.35]). The incidence of muscle cramps was significantly decreased (RR = 0.57 [95% CI, 0.45; 0.73]) after the implementation of the system, and the number of patients with 6-10 episodes dropped from 10 to 1. Multivariate analyses also showed significantly lower RRs in the intervention group: 0.29 ([95% CI, 0.20; 0.41]) for IDH and 0.58 ([95% CI, 0.45; 0.74]) for muscle cramps. Compared with the pre-intervention, participants in the intervention group had a large improvement in self-management (p < 0.001) and self-efficacy (p < 0.001). CONCLUSION: The study found that the internet-based hemodialysis management system was effective in reducing the IDH and muscle cramp events and improving self-management. It provided a significant implication for the development and application of internet-based programs in hemodialysis management.
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Hipotensão , Falência Renal Crônica , Feminino , Humanos , Hipotensão/epidemiologia , Hipotensão/etiologia , Internet , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Cãibra Muscular/complicações , Diálise Renal/efeitos adversosRESUMO
Background Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) have dramatically improved cancer therapy for many patients. Adverse kidney effects have been found to be an important complication but have unclear mechanisms. Methods We searched Embase, PubMed, and the Cochrane Library to identify potential eligible studies. All included studies were randomized controlled trials (RCTs) examining patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies (mAbs) and/or chemotherapy. The relative risk (RR) was used to assess the risk of nephrotoxic events. Results We included 27 clinical trials (15,063 patients). Compared with chemotherapy, the RR of all-grade nephritis was significantly increased with anti-PD-1/PD-L1 mAbs (RR = 2.77, 95% CI: 1.09-6.99, P = 0.03). Furthermore, anti-PD-1/PD-L1 mAbs plus chemotherapy can significantly increase the RR of all-grade nephritis (RR = 2.99, 95% CI: 1.07-8.35, P = 0.04). There was also a significant increase in the RRs of all-grade increased blood creatinine (RR = 1.88, 95% CI: 1.24-2.86, P = 0.003) and acute kidney injury (AKI) (RR =3.35, 95% CI: 1.48-7.60, P = 0.004). Conclusions Anti-PD-1/PD-L1 mAbs can significantly increase nephrotoxicity in patients with solid tumors, especially when combined with chemotherapy. During the application of these drugs, we should remain aware of nephrotoxicity for better efficacy. Trial registration number and date of registration Not applicable.
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Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/efeitos adversos , Nefropatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIMS: We aimed to assess whether the safety outcomes exerted by sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with different renal function at baseline. DATA SYNTHESIS: We searched randomized controlled trials comparing SGLT2 inhibitors with placebo in participants simultaneously involving the entire range of estimated glomerular filtration rate (eGFR) levels at baseline in one study. According to eGFR, we divided the population into two subgroups with eGFR <60 ml/min/1.73 m2 and eGFR≥60 ml/min/1.73 m2. Data from the CANVAS program, CREDENCE, EMPA-REG OUTCOME, DECLARE-TIMI 58, DAPA-HF, and EMPA-REG RENAL were included. SGLT2 inhibitors significantly reduced the risk of all serious adverse events (HR 0.91 [95% CI 0.87 to 0.95], p < 0.001) and acute kidney injury (HR 0.74 [95% CI 0.64 to 0.85], p < 0.001). Except for high risk of genital infection, SGLT2 inhibitors did not increase the risk of amputation, fracture, hyperkalemia, hypoglycemia, volume depletion, or urinary tract infection. Further analyses showed that these safety outcomes were similar between subgroups (p-interaction > 0.05). For osmotic diuresis, SGLT2 inhibitors significantly increased the risk by 75% (p = 0.036), and subgroup analyses showed that this effect was completely attributed to the increase in patients with eGFR ≥60 ml/min/1.73 m2 (p-interaction<0.001). CONCLUSION: The indication of no risk of osmotic diuresis in patients with eGFR<60 ml/min/1.73 m2 and the consistency of other safety outcomes across different baseline renal function may allow additional individuals to safely use SGLT2 inhibitors.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefropatias/fisiopatologia , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Rim/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: In order to find new strategies for the prevention of vascular calcification in uremic individuals especially treated by dialysis and develop novel therapeutic targets in vascular calcification, we explore the role of KCa3.1 in alkalinization-induced VSMCs calcification in vitro. METHOD: Rat VSMCs calcification model was established by beta-glycerophosphate (ß-GP, 10 mM) induction. The pH of Dulbecco's modified Eagle's medium (DMEM) was adjusted every 24 h with 10 mM HCl or 10 mM NaHCO3 . The mineralization was measured by Alizarin Red staining and O-cresolphthalein complex one method. mRNA and protein expression were detected by RT-PCR and Western blot or immunofluorescence. Ca2+ influx was measured by Elisa. RESULT: The results indicated that alkalization induced an increase in Ca2+ influx to enhance VSMCs calcification. Furthermore, the increase of calcification was associated with the expression of KCa3.1 via advanced expression of osteoblastic differentiation markers alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2). Blocking KCa3.1 with TRAM-34 or shRNA vector can significantly lowered the effects of calcification in the activity of ALP and Runx2 expression. CONCLUSION: Together all, our studies suggested that alkalinization can promote vascular calcification by upregulating KCa3.1 channel and enhancing osteogenic/chondrogenic differentiation by upregulating Runx2. The specific inhibitor TRAM-34 and KCa3.1-shRNA ameliorated VSMCs calcification by downregulating KCa3.1.
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Aorta/patologia , Calcinose/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Calcinose/induzido quimicamente , Calcinose/tratamento farmacológico , Cálcio/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Glicerofosfatos/toxicidade , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Masculino , Músculo Liso Vascular/química , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Pirazóis/farmacologia , Ratos Sprague-DawleyRESUMO
Vascular calcification such as arteriosclerosis, which is characterized by a calcification of the tunica media, is a severe complication of chronic kidney disease (CKD), contributing to the high prevalence of cardiovascular morbidity and mortality in patients with CKD. An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMCs), resembling osteogenesis. Metabolic acidosis, a common clinical manifestation in CKD, is known to decrease vascular calcification. To understand the underlying regulatory mechanisms of acidosis, we investigated whether the acidosis-decreased VSMC calcification involves altered signaling of the LTCC/Ca2+/Runx2 pathway. Vascular calcifications, calcium content, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), L-type calcium channel (LTCC) ß3 subunits, and calcium influx were measured in vivo or in vitro. Calcified nodules and calcium content increased either in aorta sections of vascular calcified rats or in VSMCs induced by ß-GP. The expression of Runx2 and ALP activity markedly rose, accompanied by the increasing expression of LTCC ß3 subunits and calcium influx. However, acidosis supplementation successfully attenuated VC and VSMC calcification and inhibited Runx2, ALP, LTCC ß3 subunits, and calcium influx. In conclusion, acidosis significantly attenuated vascular calcification in association with downregulation of the LTCC/Ca2+/Runx2 pathway.
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Acidose/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Calcificação Vascular/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aorta/metabolismo , Células Cultivadas , Masculino , Redes e Vias Metabólicas , RatosRESUMO
Recent studies have indicated that extracellular acid stimulation inhibited the calcification of vascular smooth muscle cells (VSMCs). Cell apoptosis played an important role in the occurrence and development of vascular calcification. We further explored the effects of Gas6/Axl or PI3K/Akt signaling pathway on the inhibition of rat VSMCs calcification in response to extracellular acid stimulation. Our study demonstrated that a high concentration of phosphorus induced apoptosis and calcification of VSMCs, decreased expression of Axl, and reduced phosphorylation of Akt. Stimulation of extracellular acid counteracted the effects as above by increasing the expression of Axl and Akt phosphorylation and decreasing the expression of activated Caspase3, which thereby decreased cell apoptosis and calcification. Moreover, the effects can be attenuated by PI3K inhibitor. Our study proved that extracellular acid stimulation played a vital role in the inhibition of rat VSMCs calcification and apoptosis in Gas6/Axl or PI3K/Akt signaling pathway.
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Indicadores e Reagentes/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Quinolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Calcinose/prevenção & controle , Caspase 3/metabolismo , Hipertensão/metabolismo , Masculino , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
As an important long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development and progression of various carcinomas. However, the role and genetic alterations of HOTAIR in gastric cardia adenocarcinoma (GCA) occurrence and progression have not been elucidated. We performed a case-control study in a population of north China to evaluate the possible association between haplotype-tagging SNPs (htSNPs) of the whole HOTAIR sequence and the risk of GCA as well as functional effect of the susceptibility single nucleotide polymorphism (SNP) rs12826786 on gene expression. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to examine the genotype of htSNPs in 515 GCA patients and 654 control subjects, and the quantitative real-time reverse transcription PCR (RT-PCR) method was used to examine the expression of HOTAIR in 102 GCA patients. A family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing GCA. Among three htSNPs of the HOTAIR gene (rs12826786 C>T, rs4759314 A>G, and rs10783618 C>T), only the T allele of rs12826786 was found to increase the risk of developing GCA and was associated with smoking habit and tumor-node-metastasis (TNM) stage. In addition, higher expression levels of HOTAIR were found in tumor tissues and rs12826786 SNP has a genotype-specific effect on HOTAIR expression. A high HOTAIR expression level was associated with poor GCA patients' survival. These results indicate that functional genotype alteration of rs12826786 SNP may influence the expression of HOTAIR, and HOTAIR may be a useful marker to predict the biological behavior of tumors and potentially a therapeutic target in GCA treatment.
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Adenocarcinoma/genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adulto , Alelos , Cárdia/patologia , China , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: The mitochondrial displacement loop (D-loop) is known to accumulate mutations and SNPs at a higher frequency than other regions of mitochondrial DNA (mtDNA). We had identified chronic kidney disease (CKD) risk-associated SNPs in the D-loop of CKD patients previously. In this study, we investigated the association of SNPs in the D-loop of mtDNA with the kidney survival of CKD. METHODS: The D-loop region of mtDNA was sequenced for 119 CKD patients from the inpatient of the Fourth Hospital of Hebei Medical University. The Kaplan-Meier method was used to identify disease outcome-associated SNPs in the D-loop of CKD patients. The Cox proportional hazards model was used to identify risk factors for the kidney survival of CKD. RESULTS: In the present study, we identified 20 SNPs with a frequency higher than 5% and assessed the relationship of these SNPs with kidney survival time in CKD patients, a SNP of 146 was identified by log-rank test for statistically significant prediction of the kidney survival time. In an overall multivariate analysis, allele 146 was identified as an independent predictor of kidney survival time in CKD patients. The survival time of kidney in the CKD patients with 146C was significantly shorter than that of kidney in CKD patients with 146T (relative risk, 2.336; 95% CI, 1.319-3.923; p = 0.001). CONCLUSION: SNPs in the D-loop can predict the kidney survival of CKD patients. Analysis of genetic polymorphisms in the mitochondrial D-loop can help to identify CKD patient subgroup at high risk of a poor disease outcome.
Assuntos
DNA Mitocondrial , Rim , Insuficiência Renal Crônica , Adulto , Idoso , Progressão da Doença , Feminino , Genes Mitocondriais , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Sobrevivência de Tecidos/genéticaRESUMO
OBJECTIVE: To explore risk factors for coronary artery calcification (CAC) inpatients with end-stage renal disease (ESRD). METHODS: A total of 53 ESRD patients undergoing regular hemodialysis (3 times a week) from August 2014 to March 2015 in the Fourth Hospital of Hebei Medical University were enrolled in the study. The patients were divided into the negative control group (13 cases) and three positive groups (11 mild calcification cases, 12 moderate calcification cases and 17 severe calcification cases) based on coronary artery calcification score (CACs). Clinical data of all patients at study entry were collected. Arterial blood samples were also collected at the start of the first hemodialysis (HD) session of the week to measure the levels of serum albumin, uric acid, calcium (Ca), phosphorus (P), magnesium, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), C reactive protein (CRP), beta-2 microglobulin (ß2-MG), free parathyroid hormone (iPTH), alkaline phosphatase, fibrinogen, hemoglobin (HGB) and ferritin. Meanwhile, levels of blood pH were detected after collecting pre- and post-HD blood samples to calculate ΔpH (post-HD pH subtracted pre-HD pH). Logistic regression analysis was performed to analyze the correlation of CACs with clinical data and previously-reported blood biochemical indicators, followed by analysis of the incidence of CAC and influential factors in ESRD patients. RESULTS: Severity of CAC was positively correlated with age (r=0.269), HD duration (r=0.341), serum calcium (r=0.358), serum phosphorus (r=0.186) and pre-HD pH (r=0.275), but negatively correlated with serum albumin (r=-0.192) and ΔpH (r=-0.302), all P<0.05. Logistic regression analysis revealed that age, HD duration, serum phosphorus level and ΔpH were independent risk factors for CAC in ESRD patients (P<0.05). In CAC positive groups, CAC was predominantly involved in the left anterior descending artery (P<0.05, P<0.01 and P<0.01 in mild, moderate and severe calcification group, respectively). CONCLUSIONS: CAC in ESRD patients seems to be affected by multiple factors, such as age, HD duration, serum phosphorus level and ΔpH. Moreover, ΔpH affects CAC mainly by pre-HD pH. Furthermore, left anterior descending artery is predominantly affected by CAC in ESRD patients.
Assuntos
Calcinose , Doença da Artéria Coronariana , Falência Renal Crônica , Diálise Renal , Proteína C-Reativa , Cálcio , LDL-Colesterol , Fibrinogênio , Humanos , Incidência , Hormônio Paratireóideo , Fósforo , Fatores de RiscoRESUMO
BACKGROUND: The mitochondrial displacement loop (D-loop) is known to accumulate mutations and single nucleotide polymorphisms (SNPs) at a higher frequency than other regions of mitochondrial DNA (mtDNA). METHODS: This is a case-control study. We sequenced SNPs in the D-loop of mtDNA and investigated their association with the risk of chronic kidney disease (CKD). RESULTS: A total of 144 SNPs referring to the positions of the Revised Cambridge Reference Sequence (rCRS) for mitochondrial genome were identified in a case-control study. The minor alleles of nucleotides 73G, 146C, 150T, 194T, 195C and 310C were associated with an increased risk for CKD patients. CONCLUSION: Analysis of genetic polymorphisms in the mitochondrial D-loop can help identify the people who are at a high risk of developing chronic kidney disease. These SNPs can be considered as potential predictors for CKD.
Assuntos
DNA Mitocondrial/química , Insuficiência Renal Crônica/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Ethylene oxide (EO) is a common chemical contaminant in the environment and associated with the occurrence of multiple clinical diseases. This study aimed to explore the association of hemoglobin ethylene oxide (HbEO) levels with the risk of albuminuria in a representative sample of US adults. In total, 3523 participants from National Health and Nutrition Examination Survey (NHANES) 2013-2016 were enrolled and classified into four groups based on HbEO. Restricted cubic spline plots and multiple logistic regression were performed to investigate the connection between HbEO levels and albuminuria, and mediation analysis was applied to elucidate the potential mechanism for the effect of HbEO concentrations on albuminuria. In the results, compared with the extreme quartile of HbEO levels, the weighted prevalence of albuminuria was significantly increased in participants with highest quartile (Q4 vs Q1, 11.2% vs 8.1%). Restricted cubic spline plots revealed that the risk of albuminuria raised non-linearly and positively with elevated HbEO level. After adjusting for confounders, the logistic regression suggested that the risk of albuminuria was enhanced by 12% for each one-unit increase in log-2-transformed HbEO (OR = 1.12, 95% CI, 1.03-1.22, P = 0.007). Moreover, the multivariate ORs (95% CIs) on albuminuria was increased across the increasing HbEO quartiles (Q4 vs Q1, OR = 1.54, 95% CI, 1.09-2.17; P for trend = 0.029). Furthermore, the impact of high HbEO level on albuminuria was partially related to inflammation markers, including white blood cells (17.2%), neutrophils (22.1%), and lymphocytes (19.5%). To sum up, our study identified that high HbEO levels increased the risk of albuminuria in representative population of US adults, and several inflammatory mediators might be potentially involved in EO-associated albuminuria.