The role of sacubitril/valsartan in abnormal renal function patients combined with heart failure: a meta-analysis and systematic analysis.

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.

Association of Vascular Calcification with Serum lncRNA H19 and Runx2 mRNA Expression in Patients with Uremia.

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.

Hypomethylation of the LncRNA H19 promoter accelerates osteogenic differentiation of vascular smooth muscle cells by activating the Erk1/2 pathways.

OBJECTIVE: Vascular calcification is a common chronic kidney disease complication. This study aimed to investigate the function of long non-coding RNA (LncRNA) H19 in vascular calcification to explore new therapeutic strategies. METHODS: We induced osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) using ß-glycerophosphate. Then, we detected the LncRNA H19 promoter methylation status and Erk1/2 pathways using methylation-specific polymerase chain reaction and western blotting, respectively. RESULTS: Compared with the control group, high phosphorus levels induced VSMC calcification, accompanied by increases in LncRNA H19 and the osteogenic marker Runx2 and reduction of the contractile phenotype marker SM22a. LncRNA H19 knockdown inhibited osteogenic differentiation and calcification of VSMCs. However, the suppressed role of VSMC calcification caused by shRNA H19 was partially reversed by simultaneous activation of the Erk1/2 pathways. Mechanically, we found that the methylation rate of CpG islands in the LncRNA H19 promoter region was significantly lower in the high-phosphorus group, and the hypomethylation state elevated LncRNA H19 levels, which in turn regulated phosphorylated Erk1/2 expression. CONCLUSIONS: LncRNA H19 promoted osteogenic differentiation and calcification of VSMCs by regulating the Erk1/2 pathways. Additionally, hypomethylation of LncRNA H19 promoter CpG islands upregulated LncRNA H19 levels and subsequently activated Erk1/2 phosphorylation.

Effects of early recovery of renal function on adverse renal outcomes and mortality in patients with acute kidney injury: a systematic review and meta-analysis.

AIM: This study intended to scrutinize the effect of RFR time on adverse renal outcomes and mortality and try to define the cutoff of early RFR. METHODS: We conducted a literature search from database inception to February 2023. Outcome measures incorporated the progression of CKD, delivery of RRT, incidence of composite renal outcomes, and mortality. And pooled results were depicted as odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 11 studies were finally selected (507,989 patients, mean follow-up, 3.89 years). The results exhibited that the crude mortality was lower in patients with early RFR (OR = 0.39, 95% CI: 0.16-0.95, P = 0.037). In addition, patients with early RFR had a lower incidence of progression to CKD (OR = 0.38, 95% CI: 0.17-0.85, P < 0.018), RRT (OR = 0.37, 95% CI: 0.20-0.71, P = 0.03), and composite renal outcomes (OR = 0.18, 95% CI: 0.15-0.20, P < 0.001). CKD progression-related events were significantly higher in patients whose renal function recovered after 7 days (OR = 0.69, 95% CI: 0.47-1.09, P = 0.112) than in those whose renal function recovered within 7 days (OR = 0.23, 95% CI: 0.06-0.92, P = 0.038), and the risk of RRT was lower in patients who recovered within 7 days (OR = 0.32, 95% CI: 0.15-0.66, P = 0.002) than in those who recovered after 7 days (OR = 0.72, 95% CI: 0.17-3.09, P = 0.654) or longer. CONCLUSION: Patients with early RFR had a lower risk of CKD progression, RRT, and composite renal outcomes, as well as lower crude mortality than those without early recovery, despite no marked difference in 30-day, 90-day, and 1-year mortality. We speculated that 7 days may be used as a cutoff for early RFR.

Circulating miR-129-3p in combination with clinical factors predicts vascular calcification in hemodialysis patients.

Background: Vascular calcification (VC) commonly occurs and seriously increases the risk of cardiovascular events and mortality in patients with hemodialysis. For optimizing individual management, we will develop a diagnostic multivariable prediction model for evaluating the probability of VC. Methods: The study was conducted in four steps. First, identification of miRNAs regulating osteogenic differentiation of vascular smooth muscle cells (VSMCs) in calcified condition. Second, observing the role of miR-129-3p on VC in vitro and the association between circulating miR-129-3p and VC in hemodialysis patients. Third, collecting all indicators related to VC as candidate variables, screening predictors from the candidate variables by Lasso regression, developing the prediction model by logistic regression and showing it as a nomogram in training cohort. Last, verifying predictive performance of the model in validation cohort. Results: In cell experiments, miR-129-3p was found to attenuate vascular calcification, and in human, serum miR-129-3p exhibited a negative correlation with vascular calcification, suggesting that miR-129-3p could be one of the candidate predictor variables. Regression analysis demonstrated that miR-129-3p, age, dialysis duration and smoking were valid factors to establish the prediction model and nomogram for VC. The area under receiver operating characteristic curve of the model was 0.8698. The calibration curve showed that predicted probability of the model was in good agreement with actual probability and decision curve analysis indicated better net benefit of the model. Furthermore, internal validation through bootstrap process and external validation by another independent cohort confirmed the stability of the model. Conclusion: We build a diagnostic prediction model and present it as an intuitive tool based on miR-129-3p and clinical indicators to evaluate the probability of VC in hemodialysis patients, facilitating risk stratification and effective decision, which may be of great importance for reducing the risk of serious cardiovascular events.

Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification.

Vascular calcification (VC) is directly related to high mortality in chronic kidney disease (CKD), and cellular apoptosis of vascular smooth muscle cells (VSMCs) is a crucial process in the initiation of VC. Microtubule affinity-regulating kinase 4 (Mark4), known as a serine/threonine protein kinase, can induce cell apoptosis and autophagy by modulating Akt phosphorylation. However, the potential functions and molecular mechanisms of Mark4 in VSMCs apoptosis and calcification need to be further explored. Initially, our data indicated that the mRNA expression of Mark4 was prominently elevated in high phosphorus-stimulated human VSMCs compared with the other members in Marks. Consistently, Mark4 expression was found to be significantly increased in the calcified arteries of both CKD patients and rats. In vitro, silencing Mark4 suppressed apoptosis-specific marker expression by promoting Akt phosphorylation, finally attenuating VSMCs calcification induced by high phosphate. Mechanically, the transcription factor Sp1 was enriched in the Mark4 promoter region and modulated Mark4 transcription. Moreover, SET domain-containing protein 8 (Setd8) was proved to interact with Sp1 and jointly participated in the transcriptional regulation of Mark4. Finally, rescue experiments revealed that Setd8 contributed to VSMCs apoptosis and calcification by modulating Mark4 expression. In conclusion, these findings reveal that Mark4 is transcriptionally activated by Sp1, which is interacted with Setd8, to promote VSMCs calcification through Akt-mediated antiapoptotic effects, suggesting that Mark4 represents a potent and promising therapeutic target for VC in CKD.

Comparative efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet for the treatment of vascular calcification in patients with haemodialysis: a systematic review and network meta-analysis.

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].

The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Sacubitril/valsartan, a new pharmacological class of angiotensin receptor neprilysin inhibitor, is beneficial to heart failure through blocking the degradation of natriuretic peptides and inhibiting renin-angiotensin-aldosterone system (RAAS) activation which also relate to the pathophysiologic mechanisms of chronic kidney disease (CKD). However, its effects on CKD remain unclear. To assess the efficacy and safety of sacubitril/valsartan for patients with CKD, we performed this meta-analysis. METHODS: The Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sacubitril/valsartan with ACEI/ARBs in patients with CKD whose estimated glomerular filtration rate (eGFR) was below 60 mL/min/1.73 m2. We adopted the Cochrane Collaboration tool for assessing the risk of bias. The effect size was estimated using the odds ratio (OR) with 95% confidence interval (CI). RESULTS: Six trials with a total of 6217 patients with CKD were included. In terms of cardiovascular events, sacubitril/valsartan attenuated the risk of cardiovascular death or heart failure hospitalization (OR: 0.68, 95% CI 0.61-0.76, P < 0.00001, I2 = 43%). With respect to renal function, sacubitril/valsartan prevented the incidence of serum creatinine (Scr) elevation among patients with CKD (OR: 0.79, 95% CI 0.67-0.95, P = 0.01, I2 = 0%). Subgroup analysis about eGFR demonstrated that with long follow-up, sacubitril/valsartan significantly decreased the number of patients with more than 50% reduction in eGFR compared with ACEI/ARBs (OR: 0.52, 95% CI 0.32-0.84, P = 0.008, I2 = 9%). In patients with CKD, the incidence of end-stage renal disease (ESRD) was reduced with sacubitril/valsartan treatment, despite no statistically significant difference between the two groups (OR: 0.59, 95% CI 0.29-1.20, P = 0.14, I2 = 0%). As for the safety, we found that sacubitril/valsartan was associated with the occurrence of hypotension (OR: 1.71, 95% CI 1.15-2.56, P = 0.008, I2 = 51%). However, there was no trend towards increasing the risk of hyperkalemia in patients who received sacubitril/valsartan (OR: 1.09, 95% CI 0.75-1.60, P = 0.64, I2 = 64%). CONCLUSION: This meta-analysis indicated that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed. Thus, sacubitril/valsartan may be a promising option for patients with CKD. Certainly, further large-scale randomized controlled trials are needed to confirm these conclusions. SYSTEMATIC REVIEW REGISTRATION: [ https://inplasy.com/inplasy-2022-4-0045/ ], identifier [INPLASY202240045].

The association of hemoglobin ethylene oxide levels with albuminuria in US adults: analysis of NHANES 2013-2016.

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.

Role of Native Defects in Fe-Doped ß-Ga2O3.

Iron impurities are believed to act as deep acceptors that can compensate for the n-type conductivity in as-grown Ga2O3, but several scientific issues, such as the site occupation of the Fe heteroatom and the complexes of Fe-doped ß-Ga2O3 with native defects, are still lacking. In this paper, based on first-principle density functional theory calculations with the generalized gradient approximation approach, the controversy regarding the preferential Fe incorporation on the Ga site in the ß-Ga2O3 crystal has been addressed, and our result demonstrates that Fe dopant is energetically favored on the octahedrally coordinated Ga site. The structural stabilities are confirmed by the formation energy calculations, the phonon dispersion relationships, and the strain-dependent analyses. The thermodynamic transition level Fe3+/Fe2+ is located at 0.52 eV below the conduction band minimum, which is consistent with Ingebrigtsen's theoretical conclusion, but slightly smaller than some experimental values between 0.78 eV and 1.2 eV. In order to provide direct guidance for material synthesis and property design in Fe-doped ß-Ga2O3, the defect formation energies, charge transitional levels, and optical properties of the defective complexes with different kinds of native defects are investigated. Our results show that VGa and Oi can be easily formed for the Fe-doped ß-Ga2O3 crystals under O-rich conditions, where the +3 charge state FeGaGai and -2 charge state FeGaOi are energetically favorable when the Fermi level approaches the valence and conduction band edges, respectively. Optical absorption shows that the complexes of FeGaGai and FeGaVGa can significantly enhance the optical absorption in the visible-infrared region, while the energy-loss function in the ß-Ga2O3 material is almost negligible after the extra introduction of various intrinsic defects.

Effects of Cu, Zn Doping on the Structural, Electronic, and Optical Properties of α-Ga2O3: First-Principles Calculations.

The intrinsic n-type conduction in Gallium oxides (Ga2O3) seriously hinders its potential optoelectronic applications. Pursuing p-type conductivity is of longstanding research interest for Ga2O3, where the Cu- and Zn-dopants serve as promising candidates in monoclinic ß-Ga2O3. However, the theoretical band structure calculations of Cu- and Zn-doped in the allotrope α-Ga2O3 phase are rare, which is of focus in the present study based on first-principles density functional theory calculations with the Perdew-Burke-Ernzerhof functional under the generalized gradient approximation. Our results unfold the predominant Cu1+ and Zn2+ oxidation states as well as the type and locations of impurity bands that promote the p-type conductivity therein. Furthermore, the optical calculations of absorption coefficients demonstrate that foreign Cu and Zn dopants induce the migration of ultraviolet light to the visible-infrared region, which can be associated with the induced impurity 3d orbitals of Cu- and Zn-doped α-Ga2O3 near the Fermi level observed from electronic structure. Our work may provide theoretical guidance for designing p-type conductivity and innovative α-Ga2O3-based optoelectronic devices.

KAP1 modulates osteogenic differentiation via the ERK/Runx2 cascade in vascular smooth muscle cells.

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.

DRAM1 plays a tumor suppressor role in clear cell renal cell carcinoma through modulating Akt signaling.

BACKGROUND: Clear cell renal carcinoma (ccRCC) is one of the most common malignant tumors worldwide. DNA damage-regulated autophagy modulator1 (DRAM1) plays an important roles in apoptosis and tumor progression. However, the role of DRAM1 in ccRCC is still unknown. In our study, we aimed to investigate the effect of DRAM1 in the progression of ccRCC. METHODS: The expression and prognostic information of DRAM1 in ccRCC were obtained by immunohistochemistry staining and bioinformatics database. Cell proliferation, migration, invasion were detected by CCK-8 assay, wound-healing and transwell assays, and the cell apoptosis was examined by tunel assay and flow cytometry analysis. Western blot was used to detect the expression of DRAM1, Bax, Bcl2, Akt, p53,E-cadherin, N-cadherin of ccRCC cells. RESULTS: Decreased expression of DRAM1 was found in ccRCC tissues, which predicted a shorter survival rate in ccRCC patient. We confirmed that DRAM1 inhibited the proliferation, migration, invasion and epithelial mesenchymal transformation (EMT), while enhanced the apoptosis of ccRCC cells. In addition, the results of inhibition of Akt signaling were consistent with the above. We further proved that DRAM1 over-expression decreased the phosphorylation of Akt signaling, and overexpression of DRAM1 could reverse oncogenic function induced by the over-activating of Akt in ccRCC cells. CONCLUSION: overexpression of DRAM1 plays a tumor suppressive role in ccRCC through inactivation of Akt and highlights the potential role of DRAM1 as a prognostic biomarker in ccRCC.

Benefit of an Internet-Based Management System among Hemodialysis Patients at the Risk of Intradialytic Hypotension and Muscle Cramps: A Controlled before and after Study.

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.

SET8, a novel regulator to ameliorate vascular calcification via activating PI3K/Akt mediated anti-apoptotic effects.

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.

LncRNA H19 sponges miR-103-3p to promote the high phosphorus-induced osteoblast phenotypic transition of vascular smooth muscle cells by upregulating Runx2.

Elucidating the mechanism of the osteogenic phenotypic transdifferentiation of vascular smooth muscle cells (VSMCs) is the key to determining the diagnosis and treatment of arterial medial calcification (AMC). Long noncoding RNAs (lncRNAs) have been reported to participate in the regulation of vascular physiology and pathology. Here, we investigated the effect and mechanism of the lncRNA H19 on the osteoblastic differentiation of VSMCs induced by high phosphorus. H19 was expressed at high levels in high phosphorus-induced primary rat VSMCs. Further experiments indicated that H19 played a positive role in the osteoblast phenotypic transition by suppressing miR-103-3p expression and subsequently promoting osteoblast-specific marker expression, including bone morphogenetic protein 2 (BMP-2) and osteopontin (OPN). Mechanistically, we recognized RUNX family transcription factor 2 (Runx2) as a direct target of miR-103-3p. Moreover, H19 directly interacted with miR-103-3p, and overexpression of miR-103-3p reversed the upregulation of Runx2 induced by H19. Therefore, H19 positively regulated Runx2 expression by sponging miR-103-3p and promoted the osteoblast phenotypic transition in VSMC calcification. Collectively, the lncRNA H19 promoted osteogenic differentiation by modulating the miR-103-3p/Runx2 axis in the process of VSMC calcification induced by a high phosphorus concentration. The current study provided new insights into an important role for the lncRNA H19 as a miRNA sponge in VSMCs and supplied novel insights into lncRNA-directed diagnostics and therapeutics for vascular calcification.

MicroRNA-103a regulates the calcification of vascular smooth muscle cells by targeting runt-related transcription factor 2 in high phosphorus conditions.

Vascular calcification, such as atherosclerosis, is a serious complication of chronic kidney disease that is characterized by tunica media calcification, and has gained increasing attention from researchers. The commonly observed association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. As microRNAs (miRNAs) have a wide range of gene regulation functions, such as cell proliferation, apoptosis, stress and transdifferentiation, the current study aimed to determine whether miRNAs play a vital role in the calcification and osteoblastic differentiation of rat thoracic aorta vascular smooth muscle cells (VSMCs). Gene expression analysis was performed on seven miRNAs (miR-29a, -30b, -103a, -125b, -133a, -143 and -211) that maybe potentially involved in the differentiation of smooth muscle cells into osteoblastic cells. The results showed that the levels of miR-29a, -30b, -103a, -125b and -143 were markedly reduced in the VSMC calcification model, particularly miR-103a, whereas runt-related transcription factor 2 (RUNX2) expression was increased. Furthermore, it was found that the expression of RUNX2 was significantly decreased following the upregulation of miR-103a, and that the expression of RUNX2 was significantly increased by downregulating miR-103a in VSMCs. Therefore, it was concluded that miR-103a plays a notable role in the transdifferentiation of the VSMCs in high phosphorus-induced calcification by targeting the regulation of RUNX2, and may therefore constitute a new target for the diagnosis and treatment of vascular calcification.

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to alkalinization-induced vascular calcification in vitro.

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.