Clinical and Experimental Hypertension最新文献

Purpose: Hyperuricemia (HUA) is an important factor leading to chronic kidney disease (CKD). The kidney tubular inflammatory response is activated in HUA. This study aimed to investigate whether lactate dehydrogenase A (LDHA) is involved in mediating uric acid-induced kidney tubular inflammatory response.

Methods: In vivo, an HUA mouse model was established by continuous intraperitoneal injection of potassium oxonate (PO) for one week. A total of 18 C57BL/6J male adult mice were divided into three groups: control group, HUA group, and HUA+oxamate group, with six mice in each group. Oxamate was intraperitoneally injected into the mice one hour after PO injection. In vitro, an HUA model was simulated by stimulating HK-2 cells with uric acid. Oxamate and tempol inhibited LDHA and reactive oxygen species (ROS) in HK-2 cells.

Results: In HUA mice, blood uric acid levels were significantly elevated. LDHA in kidney tubular cells was significantly increased in both in vivo and in vitro HUA models, accompanied by an increase in kidney tubular inflammation and ROS. Mechanistically, LDHA mediates uric acid-induced inflammation to kidney tubular cells through the ROS/NLRP3 pathway. Pharmacologic inhibition of LDHA or ROS in kidney tubular cells can significantly ameliorate inflammation response caused by uric acid.

Conclusions: LDHA in kidney tubular cells significantly was increased in HUA models. LDHA mediates kidney inflammation response induced by uric acid through the ROS/NLRP3 pathway. This study may provide a new intervention target for preventing kidney tubular inflammation caused by uric acid.

Purpose: Hypertensive disorder complicating pregnancy (HDCP) is a serious clinical disorder syndrome during pregnancy. This study aims at finding novel targets for HDCP therapy.

Methods: HDCP-related mRNAs were firstly screened out and subjected to gene enrichment analysis. We chose protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) as the research object. Thirty-nine HDCP patients at 32 to 40 weeks of gestation were selected as the HDCP group, and 39 normal controls who received cesarean section delivery at 37-42 weeks of pregnancy were enrolled in this study. Chorionic villi samples were collected within 30 min of delivery. The apoptosis of isolated placental trophoblasts was monitored to investigate the regulatory role of PRKAA2.

Results: PRKAA2 expression was further proven to be enhanced in the placental tissues of HDCP patients compared with that of normal puerpera. Subsequently, the results of flow cytometry analysis and western blot indicated that PRKAA2 overexpression accelerated primary placental cell apoptosis, while its knockdown attenuated cell apoptosis. Mechanistically, we determined that the level of PRKAA2 succinylation was elevated in the placental tissue of HDCP patients. Through in vitro succinylation assay and mutagenesis, we confirmed that sirtuin 5 (SIRT5) interacts with PRKAA2 at K69 and K260 to induce PRKAA2 desuccinylation. SIRT5 regulated primary HDCP cell apoptosis through PRKAA2. Finally, the animal study revealed that PRKAA2 elevates the systolic blood pressure of HDCP rat model.

Conclusion: Our findings indicated that SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting that PRKAA2 is a potential therapeutic target for HDCP treatment.

Objectives: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cutoff covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl^-1/mIU∙l^-1. We aimed to optimize the ARR cutoff for PA screening based on the risk of cardiovascular diseases (CVD).

Methods: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl^-1/mIU∙l^-1) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cutoff selected from FOS is applicable to PA screening.

Results: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR < 1.0, PA with ARR ≥ 1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR ≥ 1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cutoff at 2.4 ~ 4.9, 10% ~30% of PA subjects would be unrecognized although they carried a 2.45 ~ 2.58-fold higher CVD risk than essential hypertension.

Conclusions: The CVD risk-based optimal ARR cutoff is 1.0 ng·dl^-1/mIU∙l^-1 for PA screening. The current guideline-recommended ARR cutoff may miss patients with PA and high CVD risk.

Clinical trial registration: ClinicalTrials.gov (NCT03224312).

Background: Complex interconnections are evident among gut microbiota, circulating metabolites, inflammatory cytokines, and the pathogenesis of abdominal aortic aneurysms (AAA), with the causal dynamics yet to be comprehensively elucidated. The primary objective of this study was to elucidate the potential causal relationships involving gut microbiota-mediated plasma metabolites, inflammatory cytokines, and AAA.

Methods: We utilized data from genome-wide association studies predominantly comprising individuals of European ancestry, encompassing four major gut microbiota signatures, 233 plasma metabolite signatures (N = 136,016), 91 inflammatory cytokine signatures (N = 14,824), and AAA signatures (N = 1,458,875). Mendelian randomization (MR), employed in a two-sample format, was utilized as a tool to investigate the potential causal pathways from gut microbiota to the development of AAA. Additionally, a two-step MR approach was employed to dissect the impact of plasma metabolites and inflammatory cytokines on the relationship between gut microbiota and AAA and to ascertain the mediated fractions.

Results: Our findings indicate that five phylum or family-identical bacteria, 175 plasma metabolites, and seven inflammatory factors are causally associated with AAA. Among them, five bacterial species from the same phylum or family, identified from different GWAS data, were strongly associated with AAA. Of these, two exhibited negative causality and three exhibited positive causality. We found that the phylum Firmicutes and the families Oscillospiraceae might reduce the risk of AAA, whereas the families Prevotellaceae, Sutterellaceae, and Aminobacteriaceae might increase the risk of AAA. Further screening indicated that phylum Firmicutes id.1672 (GCST90017114) may confer a protective effect against AAA by reducing triglyceride levels in medium/small high-density lipoprotein (HDL).

Conclusion: MR analysis has delineated a causal pathway from gut microbiota, through plasma circulating metabolites and inflammatory cytokines, to the pathogenesis of AAA. The role of intestinal flora and certain biomarkers may provide a reference for the diagnosis of AAA, and contribute to the prevention, diagnosis, and treatment of AAA disease.

An early and accurate diagnosis of septic cardiomyopathy is vital for improving the overall prognosis of sepsis. In our research, we aimed to identify signature genes and their immune connections in septic cardiomyopathy. By analyzing the mouse myocardial transcriptome from sepsis induced by cecum ligation and puncture (CLP), we identified four distinct k-means clusters. Further analysis of human myocardial datasets using Weighted Gene Co-expression Network Analysis (WGCNA) revealed a strong correlation between the MEturquoise module and septic cardiomyopathy (cor = 0.79, p < .001). Through the application of Cytoscape plug-in MCODE and comprehensive analysis, we pinpointed two signature genes, THBS1 and TIMP1. These genes demonstrated significant involvement in immune cell infiltration, as detected by CIBERSORT, and displayed promising prognostic potential as validated by external datasets. Our experimental validation confirmed the up-regulation of both THBS1 and TIMP1 in septic murine hearts, underscoring their positive association with septic cardiomyopathy.

Background: Fibroblast growth factor 21 (FGF21) has a protective effect against cardiovascular disease. However, the role of FGF21 in hypertension remains elusive.

Methods: Ten-week-old male C57BL/6 mice were randomly divided into normal-salt (NS) group, NS+FGF21 group, deoxycorticosterone acetate-salt (DOCA) group and DOCA+FGF21 group. The mice in NS group underwent uninephrectomy without receiving DOCA and 1% NaCl and the mice in DOCA group were subjected to uninephrectomy and DOCA-salt (DOCA and 1% NaCl) treatment for 6 weeks. At the same time, the mice were infused with vehicle (artificial cerebrospinal fluid, aCSF) or FGF21 (1 mg/kg) into the bilateral paraventricular nucleus (PVN) of mice.

Results: Here, we showed that FGF21 treatment lowered DOCA salt-induced inflammation and oxidative stress in the PVN, which reduced sympathetic nerve activity and hypertension. Mechanistically, FGF21 treatment decreased the expression of HNF4α and inhibited the binding activity of HNF4α to the promoter region of ACE2 in the PVN of DOCA salt-treated mice, which further up-regulated ACE2/Ang (1-7) signals in the PVN. In addition, ACE2 deficiency abolished the protective effect of FGF21 in DOCA salt-treated mice, suggesting that FGF21-mediated antihypertensive effect was dependent on ACE2.

Conclusions: The results demonstrate that FGF21 protects against salt-sensitive hypertension via regulating HNF4α/ACE2/Ang (1-7) axis in the PVN of DOCA salt-treated mice via multi-organ crosstalk between liver, brain and blood vessels.

Background: Endothelial dysfunction of the pulmonary artery contributes to hypoxia-induced pulmonary arterial hypertension (PAH). Omentin-1, as a novel adipocytokine, plays an important protective role against cardiovascular diseases. However, the effect and underlying mechanisms of omentin-1 against PAH remain unclear.

Methods: PAH was induced in SD (Sprague & Dawley) rats via a low-oxygen chamber for 4 weeks. Hemodynamic evaluation was undertaken using a PowerLab data acquisition system, and histopathological analysis was stained with hematoxylin and eosin (H&E). Endothelial function of pulmonary artery was assessed using wire myography.

Results: We found that omentin-1 significantly improved pulmonary endothelial function in rats exposed to hypoxia and attenuated PAH. Mechanistically, we found that omentin-1 increased phosphorylated 5'‑adenosine monophosphate‑activated protein kinase (p‑AMPK) level and reduced endoplasmic reticulum (ER) stress and increased NO production in pulmonary artery from rats exposed to hypoxia. However, the effect of omentin-1 was abolished by treatment with AMPK inhibitor (Compound C).

Conclusions: Our results reveal a protective effect of omentin-1 in PAH via inhibiting ER stress through AMPKα signaling and provide an agent with translational potential for the treatment of PAH.

Objective: To elucidate the underlying mechanism by which the proliferation and migration abilities of human umbilical cord mesenchymal stem cells (hUC-MSCs) determine their therapeutic efficacy in rheumatoid arthritis treatment.

Methods: The DBA/1J mice were utilized to establish a collagen-induced RA (CIA) mouse model and to validate the therapeutic efficacy of hUC-MSCs transfected with CD151 siRNA. RNA-seq, QT-PCR and western blotting were utilized to evaluate the mRNA and protein levels of the PI3K/AKT pathway, respectively.

Results: IFN-γ significantly enhanced the proliferation and migration abilities of hUC-MSCs, up-regulating the expression of CD151, a gene related to cell proliferation and migration. Effective inhibition of this effect was achieved through CD151 siRNA treatment. However, IFN-γ did not affect hUC-MSCs differentiation or changes in cell surface markers. Additionally, transplantation of CD151-interfered hUC-MSCs (siRNA-CD151-hUC-MSCs) resulted in decreased colonization in the toes of CIA mice and worse therapeutic effects compared to empty vector treatment (siRNA-NC-hUC-MSCs).

Conclusion: IFN-γ facilitates the proliferation and migration of hUC-MSCs through the CD151/PI3K/AKT pathway. The therapeutic efficacy of siRNA-CD151-hUC-MSCs was found to be inferior to that of siRNA-NC-hUC-MSCs.

Background: Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity.

Methods: Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively.

Results: Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT₁R) expression and function in PVN. The increase in AT₁R expression levels was attributed to a decrease in the methylation level of the AT₁R promoter region, resulting in an increase in AT₁R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT₁R promoter region, which reduced mRNA and protein expression level of AT₁R, heart rate and SBP in DMO, but not in CMO.

Conclusions: The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.

Objectives: We examined the association of schooling, sibling life situation, and dietary habits with the estimated 24-h urinary salt excretion and the urinary sodium-to-potassium (Na/K) ratio in 3-year-old children.

Methods: The subjects were 639 children who underwent a health checkup in four cities and towns in Kyoto Prefecture from January to November 2019. The children's parents answered questionnaires about weekday childcare places, the birth order, and the awareness of reducing the salt intake. The questions on food intake frequency included 10 items. The estimated 24-h salt excretion and Na/K ratio were calculated from the participants' first voiding urine in the morning.

Results: Data were available for 294 children. The median (interquartile range (IQR)) of salt excretion (g/day) was 2.6 (1.7-3.4), and urinary Na/K ratio (mmol ratio) was 2.6 (1.6-4.1). Multinomial logistic regression analysis showed that the group with older siblings was significantly associated with high salt (odds ratio 1.89 (95% confidence interval 1.04 to 3.46)). In the urinary Na/K ratio, the nursery group had a significantly lower Na/K (odds ratio 0.32 (0.17 to 0.60)). High processed meat products intake was associated with a higher Na/K (odds ratio 1.96 (1.05-3.66)), whereas high vegetable intake was associated with a lower Na/K (odds ratio 0.45 (0.23-0.87)). Other factors showed no significant associations.

Conclusions: In Japanese 3-year-old children, the estimated 24-h urinary salt excretion was associated with older siblings, and the urinary Na/K ratios were associated with schooling situation and the intake of processed meat products and vegetables.