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.

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.

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.

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.

The efficacy of hemodialysis in interventional therapy in coronary artery disease patients with chronic renal insufficiency.

The aim of this study was to explore the efficacy and safety of hemodialysis in interventional therapy for patients with coronary artery disease combined with chronic renal insufficiency. With the aging and social development, the number of coronary artery disease patients with chronic renal insufficiency gradually increased. Total 58 coronary heart disease patients with chronic renal dysfunction were selected. These patients were characterized with typical angina symptoms and typical electrocardiogram (ECG) changes of onset angina. Continuous oral administration of sodium bicarbonate tablets 1 g 3/day × 3 days and slow intravenous input sodium chloride 1000 ∼1500 mL 3-12 h before operation were given. By this way, all patients were treated by hydration and alkalization. After percutaneous coronary intervention (PCI) treatment, patients were immediately transferred to undergo 4 h of dialysis treatment without removing indwelling of femoral artery puncture sheath tube to protect renal function. Changes in renal function including serum creatinine, glomerular filtration rate, and urine were observed and recorded. All patients were successfully underwent PCI treatment. Within one month after PCI, there were no obvious complication and no stent thrombosis occurred. Among of 58 patients, 56 cases showed no significant increase in serum creatinine levels compared with those before operation. However, serum creatinine level of one patient increased to 251 umol/L and one patient still required permanent dialysis. Using hemodialysis in interventional therapy in coronary artery disease patients with chronic renal insufficiency could significantly improve the prognosis of the patients.

[Prevention and Treatment of Shenkang Injection for Contrast-induced Nephropathy in Elder Patients with Chronic Kidney Disease].

Objective To explore the safety and effectiveness of Shenkang Injection (SI) for con- trast-induced nephropathy (CIN) in elderly patients with chronic kidney disease (CKD). Methods Totally 206 elderly CKD patients who were scheduled to undergo coronary angiography (CAG) were assigned to three groups according to random digit table, i.e., the rehydration therapy group (67 cases) , the SI group (71 cases) , and the control group (68 cases). Patients in the rehydration therapy group received intrave- nous dripping of normal saline 12 h before and after CAG. Patients in the SI group received intravenous drip- ping of SI, while those in the control group received intravenous dripping of 5% glucose injection. SI and 5% glucose injection was respectively used 3 days before CAG and 4 days after CAG, once per day. The inci- dence rate of CIN, and levels of creatinine, blood urea nitrogen (BUN) , serum cystatin C (CysC), kidney injury molecule-1 (KIM-1), and P2-microglobulin (P2-MG) were detected before CAG, 24 h and 96 h after CAG, respectively. Age, sex, SI, contrast dose, pre-CAG indicators of renal function were compared. Their correlations with changed 24-h creatinine value (the difference between the value at post-CAG 24 h and pre-CAG) and CIN incidence rate were analyzed using Sperman correlation and Logistic regression analy- ses. Results Compared with the rehydration therapy group and the control group, the incidence rate of CIN was significantly lower in the SI group (x2 = 5. 32, P <0. 05). Compared with before treatment in the same group, levels of creatinine and CysC were all elevated in the 3 groups after 24-and 96-h treatment (P <0. 05) ; the KIM-1 level increased in rehydration therapy group and the control group (P <0. 05) ; P2-MG level increased in the SI group (P <0.05). Compared with the control group, post-CAG P2-MG level in- creased in the SI group (P <0. 05). There was no statistical difference in other index (P >0. 05). SI was neg- atively with the incidence rate of CIN and changed 24-h creatinine value (r = -0. 612, -0. 517, P <0. 05). The contrast dose was positively with the incidence rate of CIN and changed 24-h creatinine value (r = 0. 644, 0. 562, P <0. 05). Increased contrast dose could elevate the incidence rate of CIN (P <0. 05). SI could obviously lower the incidence rate of CIN (P <0. 05). Conclusion SI could lower the incidence rate of CIN in elder CKD patients by playing certain roles in prevention and treatment.

[The effect of simvastatin on the expression of high mobility group box-1 protein in atherosclerotic rats].

OBJECTIVE: To observe the effect of simvastatin on the expression of high mobility group box-1 protein (HMGB1) and morphology of atherosclerotic plaques in atherosclerotic rats, to ascertain whether HMGB1 plays a role in the preventive mechanism of simvastatin from atherosclerosis (AS). METHODS: Sixty Wistar rats were divided randomly into three groups: control group, model group and simvastatin treatment group. Gastric gavage of vitamin D3 with high fat food was used to reproduce atherosclerotic rat model. The rats in the treatment group were treated with simvastatin of 2.5 mg x kg(-1) x d(-1) (gastric perfusion) 8 weeks after fat diet. The expression of the histopathology and protein of HMGB1 in atherosclerotic plaques of the aorta was observed by immunohistochemistry at 10 weeks and 12 weeks. The gene expression of HMGB1 at atherosclerotic plaques of aorta was observed with real time-polymerase chain reaction (RT-PCR). The morphology of the atherosclerotic plaques was observed. RESULTS: The expression of HMGB1 increased significantly in atherosclerotic plaques in model group, and simvastatin could evidently inhibit the expression of HMGB1, and it was more obvious in 12-week group. Compared with control group, the HMGB1 mRNA expression was upregulated in all atherosclerotic model groups (10 weeks: 19.695+/- 1.418 vs. 2.981+/-0.753, 12 weeks: 20.542+/-1.132 vs. 3.219+/-0.332, both P<0.01). In the simvastatin treatment group, the gene expression of HMGB1 was lower than the age-match model group at 10 weeks (15.798+/-0.891) and 12 weeks (12.641+/-0.734), and in the 12-week treatment group it was lower than that in the 10-week treatment group (P<0.05 or P<0.01). In the model group, the ring-shape calcified atherosclerotic plaques were extensively found in the wall of the aorta. Simvastatin could obviously inhibit the formation of the atherosclerotic plaques, and the effect was more obvious in the 12-week treatment group than that of the 10-week treatment group. CONCLUSION: Simvastatin can alleviate the formation of the atherosclerotic plaques in the atherosclerotic rats, decrease the protein and mRNA expression of HMGB1. The results suggest that the vessels are protected from forming AS through alleviating inflammatory reaction.

[A comparative study of the clinicopathological features in patients with IgA nephropathy with elevated uric acid level].

OBJECTIVE: To explore the changes in the clinicopathological features of patients with IgA nephropathy with elevated uric acid level. METHODS: A total of 171 patients with IgA nephropathy diagnosed at biopsy were classified into 3 groups, namely normotensive group with normal level uric acid (group 1), normotensive group with elevated uric acid level (group 2), and hypertensive group with elevated uric acid level (group 3). The clinicopathological features were compared between the 3 groups. RESULTS: From group 1 to group 3, the disease duration became elongated, body weight increased, systolic and diastolic pressures elevated, blood urea nitrogen and serum creatinine increased, glomerular filtration rate decreased, and 24-h urine protein increased; the apolipoprotein A, high-density lipoprotein and albumin levels decreased, while apolipoprotein B100, triglyceride, cholesterol and low-density lipoprotein increased. The glomerular damage, tubulointerstitial lesions and arteriole hypertrophy worsened, and Lee's grade III changes were predominant in group 1, grade III or IV in group 2 and grades III-V in group 3. Mesangial proliferative glomerulonephritis was the major pathological type in groups 1 and 2, as compared with focal segmental glomerulonephritis or sclerosing glomerulonephritis in group 3. CONCLUSION: Patients with IgA nephropathy and elevated uric acid level have greater clinicopathological damage than those with normal uric acid level, and hypertension further aggravates such damages.

[Risk factors of hypertension in IgA nephropathy].

OBJECTIVE: To explore the risk factors of hypertension in patients with IgA nephropathy in South China. METHODS: The clinical and renal pathological data of 280 primary IgA nephropathy patients diagnosed by biopsy were analyzed to extinguish the risk factors of hypertension. RESULTS: A total of 96 patients were suffered with hypertension (34.3%). A single-variable analysis showed that the age (>or= 40 years), body weight (>or= 60 kg), absence of macrohematuria, duration of disease (>or= 60 months), blood urea nitrogen >or= 8 mmol/L, serum creatinine (>or= 133 micromol/L), hyperuricaemia, degree of 24 h-proteinuria (>or= 1.5 g), segmental glomerular lesions (>or= 25%), globe glomerular sclerosis (>or= 10%), tubular atrophy (>or= 25%), interstitial fibrosis (>or= 25%), interstitial inflammation (>or= 25%) and arteriole hypertrophy (>or= 10%) were all risk factors related to hypertension; multivariate logistic regression analysis showed that serum creatinine, age, arteriole hypertrophy, body weight and 24 h-proteinuria were the independent risk factors. CONCLUSION: Many factors were related the hypertension in patients with IgA nephropathy, while serum creatinine, age, arteriole hypertrophy, body weight and 24 h-proteinuria were the independent risk factors of hypertension.