Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation.

Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.

The efficacy and safety of sertraline in maintenance hemodialysis patients with depression: A randomized controlled study.

OBJECTIVE: To determine the efficacy and safety of sertraline in maintenance hemodialysis (MHD) patients with depression. METHODS: A randomized controlled trial was conducted involving 125 MHD patients with depression. The treatment group received sertraline, while the control group did not receive any antidepressant treatment. After 12 weeks, we compared the changes in the Hamilton Depression Rating Scale (HAMD), the Medication Adherence Report Scale-5 (MARS-5), the Mini Nutritional Assessment short-form (MNA-SF), the Kidney Disease Quality of Life-36 (KDQOL-36) scores, selected clinical and laboratory indicators, and the incidence of drug-related adverse reactions between the two groups. RESULTS: After 12 weeks of treatment, the HAMD scores of patients in the treatment group significantly decreased compared to before treatment and were lower than those in the control group. The KDQOL-36, MARS-5, and MNA-SF scores in the treatment group also significantly improved compared to before treatment and were superior to those in the control group. Albumin and hemoglobin levels in the treatment group significantly increased, while C-reactive protein significantly decreased. The incidence of nausea was slightly higher in the treatment group, and was mostly relieved after reducing the dosage of sertraline. LIMITATIONS: This study is a single-center, small-sample study with a relatively short duration of treatment and follow-up. CONCLUSIONS: Sertraline can alleviate depressive symptoms, and improve the quality of life and treatment compliance of MHD patients, while improving chronic inflammation, malnutrition, and anemia. However, starting with a low dose and reducing the maintenance dose is recommended when administering sertraline.

Long non-coding RNA MALAT1 sponges miR-30c to promote the calcification of human vascular smooth muscle cells by regulating Runx2.

OBJECTIVES: Recent evidence suggested that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in the pathogenesis of vascular calcification (VC). In this study, we tried to explore the expression and role of a lncRNA, i.e., metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and a miRNA, i.e., miR-30c, in VC. METHODS: In vitro VC model was induced in human vascular smooth muscle cells (VSMCs) after 10 days culture in calcifying medium containing 2 mM Na2HPO4. Alizarin red S staining, calcium assay and western blot analysis of runt-related transcription factor 2 (Runx2) and alpha smooth muscle actin (α-SMA) were performed to evaluate VC. Knockdown of MALAT1 and up-regulation of MALAT1, miR-30c and Runx2 was performed to determine the impact of these molecules on VSMCs calcification. Dual-luciferase report assay was performed to confirm the relationship between MALAT1 and miR-30c or miR-30c and Runx2. In addition, quantitative reverse transcription PCR and western blot were used to determine gene and protein expression. RESULTS: MALAT1 was increased, while miR-30c was decreased in calcified VSMCs. Knockdown of MALAT1 suppressed VSMCs calcification; on the contrary, up-regulation of MALAT1 promoted VSMCs calcification. The effect of MALAT1 over-expression on VSMCs calcification was reversed by upregulation of miR-30c, which was reversed again by upregulation of Runx2. Dual-luciferase report assay confirmed that there is a direct interaction between MALAT1 and miR-30c, and Runx2 is a direct target of miR-30c. CONCLUSION: MALAT1 over-expression promoted VSMCs calcification, which was at least partially through regulating the miR-30c/Runx2 axis.

Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction.

Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a redox-sensitive transcription factor, is responsible for regulating cellular redox homeostasis. However, the exact role of Nrf2 in dyslipidemia-induced dysfunction of proximal tubule cells is still not fully elucidated. In the present study, we showed that palmitic acid (PA) induced mitochondrial damage, excessive mitochondrial reactive oxygen species (ROS) (mtROS) generation, and cell injury in HK-2 cells. We further found that mtROS generation was involved in PA-induced mitochondrial dysfunction, cytoskeletal damage, and cell apoptosis in HK-2 cells. In addition, we demonstrated that the Nrf2/ARE signaling pathway was activated in PA-induced HK-2 cells and that silencing Nrf2 dramatically aggravated PA-induced mtROS production, mitochondrial damage, cytoskeletal damage and cell apoptosis in HK-2 cells. However, the mitochondrial antioxidant MitoTEMPOL effectively eliminated these negative effects of Nrf2 silencing in HK-2 cells under PA stimulation. Moreover, activation of the Nrf2/ARE signaling pathway with tBHQ attenuated renal injury, significantly reduced mtROS generation, and improved mitochondrial function in rats with HFD-induced obesity. Taken together, these results suggest that the Nrf2/ARE-mediated antioxidant response plays a protective role in hyperlipidemia-induced renal injury by ameliorating mtROS-mediated mitochondrial dysfunction and that enhancing Nrf2 antioxidant signaling provides a potential therapeutic strategy for kidney injury in CKD with hyperlipidemia.

Effects and safety of Sacubitril/Valsartan (SV) on heart function and blood pressure in maintenance hemodialysis (MHD) patients.

To observe the effects and safety of Sacubitril/Valsartan (SV) on heart function and blood pressure in maintenance hemodialysis (MHD) patients with chronic heart failure (CHF). The clinical data and biochemical parameters of MHD patients were retrospectively analyzed. These MHD patients, who were collected from January 2020 to June 2021 in the Blood Purification Center of the First Affiliated Hospital of Chongqing Medical University, received SV treatment to control heart failure (HF). Altogether 54 MHD patients complicated with CHF who received SV treatment were selected for this self-controlled study. The changes of serum biochemical indexes, left anteroposterior atrial diameter (LAD), left ventricular end diastolic diameter (LVID), left ventricular ejection fraction (LVEF), right atrial transverse diameter (RAD), right anteroposterior ventricular diameter (RVD), blood pressure and antihypertensive drug dosage before and after treatment were assessed. The adverse reactions such as hyperkalemia, hypotension before dialysis, angina pectoris, myocardial infarction, cerebral infarction, cerebral hemorrhage and hospitalization due to HF were recorded before and after treatment. After treatment, LAD and LVID, incidence of angina pectoris, duration of hospitalization for HF, systolic blood pressure and diastolic blood pressure before dialysis, and the calibration value of antihypertensive drugs were all reduced, while LVEF was increased. The incidence of hyperkalemia (serum potassium >5.5 mmol/L) also increased after treatment compared with before treatment (P<0.05). The incidence of hypotension, angina pectoris, myocardial infarction, cerebral infarction and cerebral hemorrhage during treatment was similar to that before treatment (P>0.05). SV can effectively improve left atrial and left ventricular remodeling in MHD patients with CHF, improve LVEF, reduce the incidence of angina pectoris and duration of hospitalization due to HF in MHD patients, which is conducive to the control of blood pressure in MHD patients with hypertension. The incidence of hyperkalemia increased during SV treatment. SV did not increase the incidence of hypotension, myocardial infarction, cerebral infarction, cerebral hemorrhage and other events in MHD patients.

Estimation of bed shear stress and analysis of sediment resuspension in Lake Chaohu, China.

Resuspended sediment is an important carrier of underwater material circulation, and bed shear stress is usually considered to be closely related to sediment resuspension. To analyze the resuspension dynamics in severely eutrophic Lake Chaohu, China, three fixed stations were set up to collect wave, current, and suspended sediment concentrate (SSC) data under windy weather, and two significant sediment resuspension events were recorded. Based on the Gaussian-shaped spectrum characteristics of waves in Lake Chaohu, the wave orbital velocity was estimated by using the wave parameter method. The selection of the general wave spectrum is important for the accurate estimation of wave orbital velocity. The results of the simple linear wave method were very similar to those of the wave parameter method with a Gaussian-shaped spectrum in Lake Chaohu. The total bed shear stress combining waves and currents during the observation period was calculated, and most of it was contributed by wind-driven waves. The bed material of Lake Chaohu has silt-enriched and weak cohesive features, and an examination of critical shear stress showed that the modified Shields curve method was still applicable to Lake Chaohu. When a sediment resuspension event occurred, the vertical gradient of SSC increased significantly, and the peak SSC value depended on the peak value of bed shear stress. As a predictor, bed shear stress only showed a good linear relationship during sediment resuspension events. At other times, the prediction of SSC using bed shear stress may be biased, especially at the time after a significant sediment resuspension event.

Two Mn(II) and Zn(II) Coordination Polymers: Aqueous-Phase Detection of Nitroaromatic Explosives and Protective Effect on Atherosclerosis.

Via the solvothermal reaction between Zn(II) or Mn(II) salts and 5-(3,4-dicarboxylphenoxy)nicotinic acid (H3L) ligand, a trifunctional N,O-building block having three diverse kinds of functional groups (O-ether, N-pyridyl and COOH), two new coordination polymers (CPs) could be generated, and their chemical formulae respectively are {[Mn3(L)2(H2O)2]·4H2O} (1) and {[Zn(HL)]·NMP} (2). The complex 2 based on Zn(II) possesses high efficiency of fluorescence quenching for the nitrophenol (2,4,6-trinitrophenol, TNP; 4-nitrophenol, 4-NP; 3-nitrophenol, 3-NP; 2-nitrophenol, 2-NP) in the aqueous solution. Furthermore, the treatment activity of compounds on the atherosclerosis was assessed, and relevant mechanism was investigated. First of all, the ELISA assay was used to measure the content of the inflammatory cytokines released into the plasma. Besides, the levels of the NF-κb signaling pathway in the vascular endothelial cells were measured with real time RT-PCR. The hemolysis test was conducted in this research to measure the biocompatibility of the new compound.

Correlation between Levels of Serum Lipoprotein-Associated Phospholipase A2 and Soluble Suppression of Tumorigenicity 2 and Condition of Acute Heart Failure Patients and Their Predictive Value for Prognosis.

Objective: To explore the correlation between levels of serum lipoprotein-associated phospholipase A2 (LP-PLA2) and soluble suppression of tumorigenicity 2 (sST2) and condition of acute heart failure (AHF) patients and their predictive value for prognosis. Methods: The data of patients who complained of acute dyspnea and were treated in our hospital (January 2018-January 2020) were selected for review analysis, and those diagnosed with AHF by means of chest films, physical examination, cardiogram, and color Doppler ultrasonography (CDS) were selected as the study objects. The patients were split into the mild group (I or II, 55 cases) and the severe group (III or IV, 50 cases) according to the clinical condition grading standard in Guidelines for Diagnosis and Treatment of Acute Heart Failure. In addition, 105 healthy individuals examined in our medical center in the same period were selected as the control group. The serum LP-PLA2 and sST2 levels of all study objects were measured to analyze the correlation between these levels and AHF condition. Readmission due to heart failure and all-cause death were regarded as the endpoint events, and after one year of follow-up visits, the occurrence of the endpoint events in patients of the two groups was recorded, and with the endpoint events as the variable, the patients were divided into the event group and nonevent group to establish a logistic regression analysis model and analyze the merit of serum LP-PLA2 and sST2 in evaluating patient outcome. Results: The patients' general information such as age and gender between the severe group and the mild group were not statistically different (P > 0.05), and the levels of high-sensitivity c-reactive protein (CRP), hemoglobin, creatinine, and uric acid of the severe group were greatly different from those of the mild group (P < 0.001), the comparison result of serum LP-PLA2 and sST2 levels was severe group > mild group > control group (P all <0.001), and the serum LP-PLA2 and sST2 levels of the severe group were, respectively, 275.98 ± 50.68 ng/ml and 2,122.65 ± 568.65 ng/ml; among 105 AHF patients, 50 of them had endpoint events (47.6%), including 36 in the severe group (36/50, 72.0%) and 14 in the mild group (14/55, 25.5%), and the event group presented greatly higher serum LP-PLA2 and sST2 levels than in the nonevent group (P < 0.001); according to the logistic regression analysis, serum LP-PLA2 and sST2 had independent predictive value for prognosis of AHF patients, which could be used as the independent predictive factors for 1-year prognosis. Conclusion: Serum LP-PLA2 and sST2 have a good diagnosis value for the condition and prognosis of AHF patients, which shall be promoted and applied in practice.

Escore de Risco Clínico Simples para Prever a Mortalidade Pós-Alta Hospitalar em Pacientes Chineses Hospitalizados por Insuficiência Cardíaca / A Simple Clinical Risk Score to Predict Post-Discharge Mortality in Chinese Patients Hospitalized with Heart Failure

Resumo Fundamento Doenças cardiovasculares são a principal causa de morte na China. Entretanto, os esforços atuais para se identificar os fatores de risco de morte em pacientes hospitalizados com insuficiência cardíaca (IC) estão direcionados principalmente para a mortalidade durante a internação e a mortalidade após 30 dias nos Estados Unidos. Dessa forma, é necessário um modelo semelhante ao modelo utilizado para prever o risco considerado para procedimentos cirúrgicos cardiovasculares em pacientes para avaliar o risco de pacientes internados com diagnóstico de IC. Objetivo Identificar variáveis que podem prever a mortalidade por IC um ano após a alta hospitalar, e desenvolver um escore de risco para avaliar o risco de morte no período de um ano. Métodos No presente estudo, 1.742 pacientes chineses com IC foram divididos aleatoriamente em dois grupos: um grupo de amostra de derivação e um grupo de amostra de teste. O método de simulação Monte Carlo via Cadeias de Markov foi usado para identificar variáveis que podem prever a mortalidade um ano após a alta hospitalar. Variáveis com uma frequência >1% na análise bivariada, e que foram consideradas clinicamente significativas, foram qualificadas para análises de modelagens posteriores. A probabilidade posterior de que uma variável estava estatística e significativamente associada ao resultado foi calculada como o número total de vezes em que o IC de 95% da variável não coincidiu com 1 (ou seja, o ponto de referência), dividido pelo número total de iterações. Uma variável com uma probabilidade de 0,9 ou mais alta foi considerado um fator de risco robusto para prever o resultado, e foi incluída na lista final de variáveis. O nível de significância estatística adotado foi 5%. Resultados Cinco variáveis que pudessem prever de maneira robusta a mortalidade um ano após a alta hospitalar foram identificadas: idade, sexo feminino, escore da New York Heart Association (Associação de Cardiologia de Nova Iorque) >3, diâmetro do átrio esquerdo, e índice de massa corporal. Os modelos de derivação e de teste tiveram uma área de curva característica de operação do receptor de 0,79. Essas variáveis selecionadas foram utilizadas para avaliar o escore de risco de mortalidade por IC após um ano, e este foi dividido em três grupos (baixo, moderado e alto). O grupo de alto risco corresponde a aproximadamente 86% das mortes, e o grupo de risco moderado corresponde a 12% das mortes. Conclusão Um escore de risco de 5 variáveis simples pode ser utilizado para avaliar a mortalidade um ano após a alta hospitalar de pacientes internados com IC.

Abstract Background Cardiovascular diseases are the leading causes of death in China. However, present efforts to identify the risk factors for death in patients hospitalized with heart failure (HF) are primarily focused on in-hospital mortality and 30-day mortality in the United States. Thus, a model similar to the model used for predicting the risk in patients considered for cardiovascular surgical procedures is needed to evaluate the risk of the patients admitted with a diagnosis of HF. Objective To identify variables that can predict post-discharge one-year HF mortality and develop a risk score to assess the risk of dying within one year. Methods In the present study, 1,742 Chinese patients with HF were randomly divided into two groups: a derivation sample group and a test sample group. A Markov Chain Monte Carlo simulation method was used to identify variables that can predict the one-year post-discharge mortality. Variables with a frequency of >1% in the bivariate analysis and that were considered clinically meaningful were eligible for further modeling analyses. The posterior probability that a variable was statistically and significantly associated with the outcome was calculated as the total number of times that the variable's 95% CI did not overlap with 1 (i.e., the reference point) divided by the total number of iterations. A variable with a probability of 0.9 or higher was considered a robust risk factor for predicting the outcome, and this was included in the final variable list. The level of statistical significance adopted was 5%. Results Five variables that could robustly predict the one-year post-discharge mortality were identified: age, female gender, New York Heart Association functional classification score >3, left atrial diameter, and body mass index. Both derivation and test models had a receiver operating curve area of 0.79. These selected variables were used to assess the one-year HF mortality risk score, and these were divided into three groups (low, moderate, and high). The high-risk group corresponds to nearly 86% of the deaths, while the moderate group corresponds to 12% of the deaths. Conclusion A simple 5-variable risk score can be used to assess the one-year post-discharge mortality of hospitalized Chinese patients with HF.

A Simple Clinical Risk Score to Predict Post-Discharge Mortality in Chinese Patients Hospitalized with Heart Failure. / Escore de Risco Clínico Simples para Prever a Mortalidade Pós-Alta Hospitalar em Pacientes Chineses Hospitalizados por Insuficiência Cardíaca.

BACKGROUND: Cardiovascular diseases are the leading causes of death in China. However, present efforts to identify the risk factors for death in patients hospitalized with heart failure (HF) are primarily focused on in-hospital mortality and 30-day mortality in the United States. Thus, a model similar to the model used for predicting the risk in patients considered for cardiovascular surgical procedures is needed to evaluate the risk of the patients admitted with a diagnosis of HF. OBJECTIVE: To identify variables that can predict post-discharge one-year HF mortality and develop a risk score to assess the risk of dying within one year. METHODS: In the present study, 1,742 Chinese patients with HF were randomly divided into two groups: a derivation sample group and a test sample group. A Markov Chain Monte Carlo simulation method was used to identify variables that can predict the one-year post-discharge mortality. Variables with a frequency of >1% in the bivariate analysis and that were considered clinically meaningful were eligible for further modeling analyses. The posterior probability that a variable was statistically and significantly associated with the outcome was calculated as the total number of times that the variable's 95% CI did not overlap with 1 (i.e., the reference point) divided by the total number of iterations. A variable with a probability of 0.9 or higher was considered a robust risk factor for predicting the outcome, and this was included in the final variable list. The level of statistical significance adopted was 5%. RESULTS: Five variables that could robustly predict the one-year post-discharge mortality were identified: age, female gender, New York Heart Association functional classification score >3, left atrial diameter, and body mass index. Both derivation and test models had a receiver operating curve area of 0.79. These selected variables were used to assess the one-year HF mortality risk score, and these were divided into three groups (low, moderate, and high). The high-risk group corresponds to nearly 86% of the deaths, while the moderate group corresponds to 12% of the deaths. CONCLUSION: A simple 5-variable risk score can be used to assess the one-year post-discharge mortality of hospitalized Chinese patients with HF.

FUNDAMENTO: Doenças cardiovasculares são a principal causa de morte na China. Entretanto, os esforços atuais para se identificar os fatores de risco de morte em pacientes hospitalizados com insuficiência cardíaca (IC) estão direcionados principalmente para a mortalidade durante a internação e a mortalidade após 30 dias nos Estados Unidos. Dessa forma, é necessário um modelo semelhante ao modelo utilizado para prever o risco considerado para procedimentos cirúrgicos cardiovasculares em pacientes para avaliar o risco de pacientes internados com diagnóstico de IC. OBJETIVO: Identificar variáveis que podem prever a mortalidade por IC um ano após a alta hospitalar, e desenvolver um escore de risco para avaliar o risco de morte no período de um ano. MÉTODOS: No presente estudo, 1.742 pacientes chineses com IC foram divididos aleatoriamente em dois grupos: um grupo de amostra de derivação e um grupo de amostra de teste. O método de simulação Monte Carlo via Cadeias de Markov foi usado para identificar variáveis que podem prever a mortalidade um ano após a alta hospitalar. Variáveis com uma frequência >1% na análise bivariada, e que foram consideradas clinicamente significativas, foram qualificadas para análises de modelagens posteriores. A probabilidade posterior de que uma variável estava estatística e significativamente associada ao resultado foi calculada como o número total de vezes em que o IC de 95% da variável não coincidiu com 1 (ou seja, o ponto de referência), dividido pelo número total de iterações. Uma variável com uma probabilidade de 0,9 ou mais alta foi considerado um fator de risco robusto para prever o resultado, e foi incluída na lista final de variáveis. O nível de significância estatística adotado foi 5%. RESULTADOS: Cinco variáveis que pudessem prever de maneira robusta a mortalidade um ano após a alta hospitalar foram identificadas: idade, sexo feminino, escore da New York Heart Association (Associação de Cardiologia de Nova Iorque) >3, diâmetro do átrio esquerdo, e índice de massa corporal. Os modelos de derivação e de teste tiveram uma área de curva característica de operação do receptor de 0,79. Essas variáveis selecionadas foram utilizadas para avaliar o escore de risco de mortalidade por IC após um ano, e este foi dividido em três grupos (baixo, moderado e alto). O grupo de alto risco corresponde a aproximadamente 86% das mortes, e o grupo de risco moderado corresponde a 12% das mortes. CONCLUSÃO: Um escore de risco de 5 variáveis simples pode ser utilizado para avaliar a mortalidade um ano após a alta hospitalar de pacientes internados com IC.

Changes of serum advanced glycation end products (AGEs), matrix metalloprotein-2 (MMP-2), and urinary microalbuminuria (mALB) in diabetic nephropathy and their predictive value for heart failure.

BACKGROUND: Diabetic nephropathy is a common complication in diabetic patients, with a high rate of disability and mortality. This study aims to explore the changes in serum advanced glycation end products (AGEs), matrix metalloprotein-2 (MMP-2), and urinary microalbuminuria (mALB) in diabetic nephropathy and their predictive value for heart failure. METHODS: The 134 patients with diabetic nephropathy treated in our hospital from January 2014 to December 2017 were enrolled and divided into two groups resulting in 64 cases in an observation group with heart failure, and 70 cases without heart failure in a control group. In addition, 80 patients with simple diabetes who were treated during the same period were selected as the simple diabetes group. Levels of AGEs, MMP-2, and mALB between the groups were compared, risk factors affecting diabetic nephropathy patients with heart failure were analyzed, and an ROC curve was drawn to evaluate the predictive value of AGEs, MMP-2, and mALB for heart failure. RESULTS: The levels of AGEs and mALB in the diabetic nephropathy group were significantly higher than those in the simple diabetes group, and the levels of MMP-2 were significantly lower than those in the simple diabetes group (P<0.05). The levels of AGEs and mALB in the observation group were significantly higher than those in the control group, and the levels of MMP-2 were significantly lower than that in the control group (P<0.05). Smoking history hypertension history, blood creatinine (abnormal increase), blood uric acid (abnormal increase), AGEs (abnormal increase), MMP-2 (abnormal decrease), and mALB (abnormal increase) were independent risk factors affecting diabetic nephropathy patients with heart failure. The area under the ROC curve of AGEs, MMP-2, mALB, and their combined detection were: 0.821, 0.909, 0.897, and 0.991, respectively, showing the area under the curve of combined detection to be the largest. CONCLUSIONS: AGEs, MMP-2, and mALB have high predictive value for heart failure in patients with diabetic nephropathy. Their sensitivity and specificity are high, indicating they may hold considerable clinical value.

Dysfunction of the Klotho-miR-30s/TRPC6 axis confers podocyte injury.

Klotho deficiency was observed in virtually all kinds of kidney disease and is thought to play a critical role in podocyte injury. However, the underline mechanisms involved in podocyte injury remain unknown. miRNAs have diverse regulatory roles, and miR-30 family members were essential for podocyte homeostasis. Our study revealed that Klotho and miR-30s were downregulated in PAN-treated podocytes. The ectopic expression of Klotho ameliorates PAN induced podocyte apoptosis through upregulating miR-30a and downregulating Ppp3ca, Ppp3cb, Ppp3r1, and Nfact3 expression, which are the known targets of miR-30s. We also found that Klotho regulates TRPC6 via miR-30a to activate calcium/calcineurin signaling. Further, glucocorticoid (Dexamethasone, DEX) was found to sustain Klotho and miR-30a levels during PAN treatment in vitro. Eventually, in rats, PAN treatment substantially downregulated Klotho and miR-30a levels, lead to podocyte injury and increased proteinuria. The transfer of exogenous Klotho to podocytes of PAN-treated rats could increase miR-30a expression, reduce TRPC6 expression, and also ameliorated podocyte injury and proteinuria. In conclusion, Klotho, acting on miR-30s, which directly regulates its target genes, contributes to podocyte apoptosis induced by PAN. It is a novel mechanism underlying PAN-induced podocyte injury.

A meta-analysis of the effects of endothelial nitric oxide synthase 4ba polymorphism on renal interstitial fibrosis in diabetic nephropathy.

BACKGROUND: This study aimed to investigate the relationship between endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphism and renal interstitial fibrosis in patients with diabetic nephropathy (DN) via a meta-analysis, in the hope of providing guidance for the genotypic detection of DN. METHODS: The Boolean logic search method was adopted. A literature search of PubMed, Medline, CNKI, and other databases from inception to June 2020 was performed using the search terms "eNOS 4b/a", "diabetes", "renal interstitial fibrosis", and "kidney disease". Literatures with a DN group, a non-nephropathy diabetic group, and a normal control group were screened. Review Manager software was employed to perform the meta-analysis. RESULTS: A total of 13 articles were included in the meta-analysis, the majority of which had a low risk of bias (i.e., medium and high quality). The results of the meta-analysis indicated that the genotypic distribution frequency of eNOS4bb in patients with DN was significantly lower than that in the non-nephropathy diabetic group (Z=3.19, P=0.001). The genotypic distribution frequency of eNOS4aa was significantly higher in non-nephropathy diabetic patients than in the normal control group (Z=2.57, P=0.01). The genotypic distribution frequency of eNOS4ba was not statistically different between patients with DN and non-nephropathy diabetic patients (Z=1.45, P=0.15). The genotypic distribution frequency of eNOS4bb in DN patients was significantly lower than that in the normal control group (Z=3.03, P=0.002); however, the genotypic distribution frequency of eNOS4ba was significantly greater than that of the normal controls (Z=2.36, P=0.02), as was that of eNOS4aa (Z=2.34, P=0.02). CONCLUSIONS: Genotypic polymorphism of eNOS 4b/a was closely related to DN. Moreover, the genotypic distribution frequency of eNOS4bb in DN renal interstitial patients was lower than that in non-nephropathy diabetic patients and normal controls.

Effect of Erythropoietin on Calcification of Vascular Smooth Muscle Cells and Its Molecular Regulatory Mechanism.

To investigate its effect and molecular regulatory mechanism on vascular calcification, EPO was added to vascular smooth muscle cells cultured in vitro and injected intraperitoneally into SD rats. The effect of EPO on VSMC calcification was determined by alizarin red staining and ALP activity. Differentially expressed genes were screened by transcriptome sequencing and the relationship and function were verified. We found EPO promotes VSMC calcification in vitro and blood calcification in vivo in a dose-dependent manner. A total of 88 upregulated genes and 59 downregulated genes were detected in transcriptome sequencing, among which the expression of genes associated with bone formation exhibited a marked increase, namely the GATA6 transcription factor, BMP2, RUNX2, OPN, and OCN. Dual luciferase assay has indicated that the binding of GATA6 to BMP2 promoter facilitates the transcription of BMP2. Taken together, findings indicate that EPO can enhance the calcification of VSMCs by activating the GATA6/BMP2 signal axis.

The CX3CL1/CX3CR1 axis is upregulated in chronic kidney disease and contributes to angiotensin II-induced migration of vascular smooth muscle cells.

BACKGROUND: The role of the chemokine axis, CX3CL1/CX3CR1, in the development of cardiovascular diseases has been widely speculated. Angiotensin II (Ang II) is a pivotal factor promoting cardiovascular complications in patients with chronic kidney disease (CKD). Whether there is a link between the two in CKD remains unclear. METHODS: The uremic mice were treated with losartan for 8 weeks, and the expression of aortic CX3CL1/CX3CR1 was detected. Cultured mouse aortic vascular smooth muscle cells (VSMCs) were stimulated with Ang II, and then CX3CR1 expression was assessed by western blot. After the targeted disruption of CX3CR1 by transfection with siRNA, the migration of VSMCs was detected by transwell assay. Finally, both the activation of Akt pathway and the expression of IL-6 were detected by western blot. RESULTS: Losartan treatment reduced the upregulation of aortic CX3CL1/CX3CR1 expression in uremic mice. In vitro, Ang II significantly upregulated CX3CR1 expression in VSMCs. Targeted disruption of CX3CR1 attenuated Ang II-induced migration of VSMCs. In addition, the use of CX3CR1-siRNA suppressed Akt phosphorylation and IL-6 production in VSMCs stimulated by Ang II. CONCLUSIONS: The aortic CX3CL1/CX3CR1 is upregulated by Ang II in CKD, and it contributes to Ang II-induced migration of VSMCs in vitro.

Differential expression of miR-142-3p protects cardiomyocytes from myocardial ischemia-reperfusion via TLR4/NFkB axis.

Our research aims to explore the impact of miR-142 on myocardial apoptosis in the mouse ischemia and reperfusion (IR) model and investigate the underlying mechanisms at the molecular level. A considerable downregulation of miR-142 was observed in the cardiac area of mice post IR modeling. To understand the regulatory function of IR-induced miR-142 downregulation, the animals were categorized into four groups: IR model group; IR + agomir-142 group (IR mice treated with agomir-142); IR + antagomir-142 group (IR mice treated with antagomir-142); IR + agomir-142 + negative control (NC) group (IR mice processed with agomir-NC). The results indicated that agomir-142 upregulation was capable of shrinking IR damage-triggered infarction of the ventriculus sinister, strengthening myocardial function, and guarding against cardiomyocyte apoptosis, whereas further decreased miR-142 with antagomir-142 infection displayed negative influence of miR-142 against mice IR damage. In the cellular assay, miR-142 overexpression significantly improved proliferation and inhibited the apoptosis of neonatal rat cardiomyocytes (NRCs). Moreover, we found that miR-142 reduced the Bcl-2/Bax ratio and upregulated hydrogen peroxide (H2 O2 )-induced caspase-3 expression. Furthermore, transfection with an miR-142 mimic prevented the upregulation of TLR4/NFkB expression and activation in H2 O2 -treated NRCs. Our findings also revealed that miR-142 is linked to the 3'-untranslated area of the TLR4 gene. In addition, TLR4 overexpression considerably ablated the protective effects of miR-142 in terms of the cell viability of H2 O2 -treated NRCs. Taken together, miR-142 agomir injection in mice and miR-142 mimic transfection in NRCs plays a role in protecting the heart from IR damage and malfunction via the TLR4/NFkB axis both in vivo and in vitro.

The Efficacy of Mesenchymal Stem Cells for Cardiomyopathy: A Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: The efficacy of mesenchymal stem cells (MSCs) for cardiomyopathy remains controversial. We conducted a systematic review and meta-analysis to explore the influence of MSCs versus placebo on the treatment efficacy of cardiomyopathy. METHODS: We searched PubMed, EMbase, Web of Science, EBSCO, and Cochrane Library databases through November 2018 for randomized controlled trials (RCTs) assessing the treatment efficacy of MSCs versus placebo for cardiomyopathy. This meta-analysis was performed using the random-effect model. RESULTS: Five RCTs were included in the meta-analysis. Overall, compared with the control group for cardiomyopathy, MSCs treatment showed significantly positive effect on LVEF (MD = 5.85; 95% CI = 3.88 to 7.83; P < .00001), NYHA classification (MD = -1.11; 95% CI = -1.45 to -0.77; P < .00001), LVEDd (MD = -3.00; 95% CI = -5.37 to -0.64; P = .01), and the proportion of fixed defects (MD = -4.22; 95% CI = -6.91 to -1.52; P = .002), but had no obvious influence on death (RR = 0.42; 95% CI = 0.12 to 1.50; P = 0.18) or adverse events (RR = 1.14; 95% CI = 0.70 to 1.86; P = .59). CONCLUSION: MSCs treatment showed favorable impact on LVEF, NYHA classification, LVEDd, and the proportion of fixed defects for cardiomyopathy patients.

UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production.

Uncoupling protein 2 (UCP2), an anion transporter, modulates the production of mitochondrial reactive oxygen species (ROS) and plays an important role in protecting against cell apoptosis. However, the role of UCP2 in sepsis-associated AKI remains unclear. In the present study, we investigated the role of UCP2 in LPS-induced AKI in vitro and in vivo. UCP2 expression was increased in tubular epithelial cells (TECs) treated with LPS. Accordingly, UCP2 expression was distinctly upregulated in renal tissues from the animals with LPS-induced AKI. Furthermore, UCP2 silencing dramatically aggravated LPS-induced apoptosis, accompanied by increased ROS production in renal tubular epithelial cell. Additionally, the inhibition of UCP2 by genipin, a specific UCP2 inhibitor, exacerbated the kidney injury of animals with LPS-induced AKI. Moreover, NAC (N-acetylcysteine), a potent ROS scavenger, obviously suppressed apoptosis induced by UCP2 silencing, which suggests that the increased ROS levels were associated with tubular epithelial cell apoptosis induced by UCP2 silencing. Therefore, UCP2 exerts a protective effect on the LPS-induced apoptosis of tubular epithelial cells by reducing excess ROS production. In conclusion, our findings highlight the renoprotective actions of UCP2 on inhibiting the production of apoptotic factors and oxidative stress to improve tubular cell survival in the LPS-induced AKI model.

Effects of inhibitors of the renin-angiotensin system on reducing blood pressure and expression of inflammatory factors in CHD patients: A network meta-analysis.

The renin-angiotensin system (RAS) is an ever-evolving endocrine system with considerable checks and balances on the production and catabolism of angiotensin peptides most likely due to the manifold effects of angiotensins. We aimed to explore the effects of different inhibitors of RAS on blood pressure and expression of inflammatory factors in patients with coronary heart disease (CHD). We initially searched PubMed, EMBASE and Cochrane Library electronic databases with nine eligible randomized controlled trials enrolled. Direct and indirect evidence was combined to calculate the weighted mean difference value and draw surface under the cumulative ranking curves. The results demonstrated that, compared with placebo and enalapril, ramipril had a better effect on reducing systolic blood pressure after short-term usage of drugs (<12 months), while perindopril had better effects on reducing diastolic blood pressure and C-reactive protein expression. Furthermore, after long-term usage of drugs (≥12 months), there was no significant difference among olmesartan, quinapril and candesartan in the treatment of patients with CHD. Perindopril and ramipril had better effects on inhibiting blood pressure and expression of inflammatory factors among eight inhibitors after short-term usage of drugs (<12 months); while quinapril had better effects on reducing blood pressure and expression of inflammatory factor after long-term usage of drugs, and there was little difference in the effects between olmesartan and candesartan (≥12 months). Perindopril may have better short-term effects on reducing blood pressure and expression of inflammatory factor, while quinapril may have better long-term effects on reducing blood pressure and expression of inflammatory factor.

A blockade of PI3Kγ signaling effectively mitigates angiotensin II-induced renal injury and fibrosis in a mouse model.

Chronic kidney disease (CKD) poses a formidable challenge for public healthcare worldwide as vast majority of patients with CKD are also at risk of accelerated cardiovascular disease and death. Renal fibrosis is the common manifestation of CKD that usually leads to end-stage renal disease although the molecular events leading to chronic renal fibrosis and eventually chronic renal failure remain to be fully understood. Nonetheless, emerging evidence suggests that an aberrant activation of PI3Kγ signaling may play an important role in regulating profibrotic phenotypes. Here, we investigate whether a blockade of PI3Kγ signaling exerts any beneficial effect on alleviating kidney injury and renal fibrosis. Using a mouse model of angiotensin II (Ang II)-induced renal damage, we demonstrate that PI3Kγ inhibitor AS605240 effectively mitigates Ang II-induced increases in serum creatinine and blood urea nitrogen, renal interstitial collagen deposition, the accumulation of ECM proteins and the expression of α-Sma and fibrosis-related genes in vivo. Mechanistically, we reveal that AS605240 effectively inhibits Ang II-induced cell proliferation and phosphorylation of Akt in fibroblast cells. Furthermore, we demonstrate that Ang II-upregulated expression of IL-6, Tnf-α, IL-1ß and Tgf-ß1 is significantly attenuated in the mice treated with AS605240. Taken together, our results demonstrate that PI3Kγ may function as a critical mediator of Ang II-induced renal injury and fibrosis. It is thus conceivable that targeted inhibition of PI3Kγ signaling may constitute a novel therapeutic approach to the clinical management of renal fibrosis, renal hypertension and/or CKD.