endothelin-1 and Hyperuricemia

To study correlations between severity of hyperuricemia, endothelial dysfunction (ED) and arterial atherosclerosis (AS).. A total of 50 patients with essential hypertension of degree I-II free of associated clinical conditions entered the trial. The study group consisted of 40 patients with hyperuricemia, the control group of 10 patients with normal blood serum levels of uric acid.. The study group patients versus controls had significantly higher albuminuria (93.5 +/- 1.7 and 60.7 +/- 2.2 mg/l; p < 0.001), plasmic concentration of endotheline-1 (6.8 +/- 0.3 and 4.9 +/- 0.2 pg/ml; p < 0.001)and thickness of the intima-media complex of the common carotid artery (1.36 +/- 0.02 and 1.1 +/- 0.04; p < 0.001). All the indices correlated directly and significantly.. Patients with arterial hypertension of the first-second degree with persistent elevated levels of uric acid in blood serum had significantly higher levels of ED markers: albuminuria, plasmic endothelin concentration. Hyperuricemia and ED in such patients lead to more active progression of atherosclerotic vascular lesion.

Topics: Adult; Albuminuria; Carotid Intima-Media Thickness; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Hyperuricemia; Kidney Diseases; Male; Middle Aged; Uric Acid

This study was to observe the effect of Sodium TanshinoneⅡA Sulfonate (ST-ⅡAS) on blood uric acid (UA), human Soluble Intercellular Adhesion Molecule-1 (sICAM-1), Endothelin-1 (ET-1) and percentage of brachial artery Flow-Mediated Dilatation (FMD) in individuals with Hyperuricemia Complicated Coronary Heart Disease (HC-CHD). The study's participants were 108 patients with HC-CHD who attended our hospital between January 2020 and June 2022. In the trial, the patients were split into two groups with 54 instances each: the general group and the observation group. The observation group received ST-IIAS therapy, while the general group received standard care. The experiment chose to observe and compare the difference of uric acid, sICAM-1, ET-1, FMD, therapeutic effectiveness and negative effects between the two groups at various times. Results showed that on the 14th day, the observation group's amounts of UA, sICAM-1, and ET-1 were inferior to the general group (P<0.05); On the 7th and 14th days, the observation group's amount of ET-1 was lower than that of the general group (P<0.05); The observation group's FMD of patients on the 14th day was inferior to the general group after treatment (P<0.05); The observation group's overall effective rate was 94.44% higher than the general group's (P<0.05); The observation group experienced fewer negative responses than the general group did (P<0.05). In conclusion, ST-ⅡAS can be used for uric acid, vascular endothelial systolic and diastolic function in patients with HC-CHD, and has better clinical efficacy and lower risk of adverse reactions.

Topics: Alkanesulfonates; Coronary Disease; Dilatation; Endothelin-1; Humans; Hyperuricemia; Uric Acid

Uric acid (UA) plays important roles in inducing renal inflammation, intra-renal vasoconstriction and renal damage. Endothelin-1 (ET-1) is a well-known profibrotic factor in the kidney and is associated with fibroblast expansion. We examined the role of hyperuricemia conditions in causing elevation of ET-1 expression and kidney injury.. Hyperuricemia was induced in mice using daily intraperitoneal injection of uric acid 125 mg/Kg body weight. An NaCl injection was used in control mice. Mice were euthanized on days-7 (UA7) and 14 (UA14). We also added allopurinol groups (UAL7 and UAL14) with supplementation of allopurinol 50 mg/Kg body weight orally. Uric acid and creatinine serum were measured from blood serum. Periodic Acid Schiff (PAS) and Sirius Red staining were done for glomerulosclerosis, tubular injury and fibrosis quantification. mRNA expression examination was performed for nephrin, podocin, preproEndothelin-1 (ppET-1), MCP-1 and ICAM-1. PDGFRβ immunostaining was done for quantification of fibroblast, while α-SMA immunostaining was done for localizing myofibroblast. Western blot analysis was conducted to quantify TGF-β1, α-SMA and Endothelin A Receptor (ETAR) protein expression.. Uric acid and creatinine levels were elevated after 7 and 14 days and followed by significant increase of glomerulosclerosis and tubular injury score in the uric acid group (p < 0.05 vs. control). Both UA7 and UA14 groups had higher fibrosis, tubular injury and glomerulosclerosis with significant increase of fibroblast cell number compared with control. RT-PCR revealed down-regulation of nephrin and podocin expression (p < 0.05 vs. control), and up-regulation of MCP-1, ET-1 and ICAM-1 expression (p < 0.05 vs. control). Western blot revealed higher expression of TGF-β1 and α-SMA protein expression. Determination of allopurinol attenuated kidney injury was based on reduction of fibroblast cell number, inflammation mediators and ppET-1 expression with reduction of TGF-β1 and α-SMA protein expression.. UA induced glomerulosclerosis, tubular injury and renal fibrosis with reduction of podocyte function and inflammatory mediator elevation. ET-1 and fibroblast expansion might modulate hyperuricemia induced renal fibrosis.

Topics: Acute Kidney Injury; Animals; Cell Proliferation; Endothelin-1; Fibroblasts; Gene Expression; Hyperuricemia; Inflammation; Mice; Uric Acid

Endothelial dysfunction is defined as impairment of the balance between endothelium-dependent vasodilation and constriction. Despite evidence of uric acid-induced endothelial dysfunction, a relationship with insulin resistance has not been clearly established. In this study, we investigated the role of vascular insulin resistance in uric acid-induced endothelial dysfunction. Uric acid inhibited insulin-induced endothelial nitric oxide synthase (eNOS) phosphorylation and NO production more substantially than endothelin-1 expression in HUVECs, with IC50 of 51.0, 73.6, and 184.2, respectively. Suppression of eNOS phosphorylation and NO production by uric acid was PI3K/Akt-dependent, as verified by the transfection with p110. Treatment of rats with the uricase inhibitor allantoxanamide induced mild hyperuricemia and increased mean arterial pressure by 25%. While hyperuricemic rats did not show systemic insulin resistance, they showed impaired vasorelaxation induced by insulin by 56%. A compromised insulin response in terms of the Akt/eNOS pathway was observed in the aortic ring of hyperuricemic rats. Coadministration with allopurinol reduced serum uric acid levels and blood pressure and restored the effect of insulin on Akt-eNOS pathway and vasorelaxation. Taken together, uric acid induced endothelial dysfunction by contributing to vascular insulin resistance in terms of insulin-induced NO production, potentially leading to the development of hypertension.-Choi, Y.-J., Yoon, Y., Lee, K.-Y., Hien, T. T., Kang, K. W., Kim, K.-C., Lee, J., Lee, M.-Y., Lee, S. M., Kang, D.-H., Lee, B.-H. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis.

Topics: Animals; Arterial Pressure; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Hyperuricemia; Insulin; Insulin Resistance; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Uric Acid; Vasodilation

To identify the risk factors of kidney injuries in hypertensive patients with uric acid (UA) metabolic disorders in order to choose the optimal management tactics, by analyzing the changes in markers for endothelial dysfunction (endothelin-1 (ET-1), microalbuminuria (MAU), intima-media thickness (IMT)) and tubulointerstitial tissue lesion (beta2-microglobulin (beta2-MG, monocyte chemotactic protein-1 (MCP-1)).. Eighty-one patients with grade 1 hypertension without associated diseases, diabetes mellitus, or metabolic syndrome were examined. There were 3 study groups: 1) hyperuricosuria (n = 7); 2) hyperuricemia (n = 53); 3) hyperuricemia and renal failure (n = 6); and a control group of 15 hypertensive patients without UA metabolic disorders who were matched for age and gender with the patients of the study groups.. The hypertensive patients with hyperuricemia, as compared with those without UA metabolic disorders, showed higher plasma concentrations of ET-1 (p = 0.003) and MAU (p = 0.009) and more marked increases in common carotid IMT (p = 0.044), urinary excretion of beta2-MG (p = 0.010), and MCP-1 (p = 0.030). There were direct correlations between all the examined biomarkers and the degree of uricemia (Rs = 0.453; p < 0.001; Rs = 0.411; p < 0.001; Rs = 0.322; p = 0.067; Rs = 0.537; p < 0.001; and Rs = 0.318; p = 0.004, respectively) and between the markers of endothelial dysfunction and those of tubulointerstitial tissue lesion (Rs = 0.295 for ET-1 and MCP-1; p = 0.008; Rs = 0.399 for ET-1 and beta2-MG; p < 0.001; Rs = 0.462 for MAU and beta2-MG; p < 0.001; and Rs = 0.188 for MAU and MCP-1; p = 0.094). Multivariate analysis of the clinical and laboratory parameters under study confirmed the role of serum MCP-1, beta2-MG, MAU, creatinine levels as independent predictors for decreased relative urinary gravity, the clinical sign of tubulointerstitial tissue lesion/fibrosis, and that of a wider range of the indicators, such as MAU, ventricular septal thickness, glomerular filtration rate, relative urinary gravity, systolic blood pressure, MPC-1, low-density lipoproteins, as risk factors for renal filtrating dysfunction.

Topics: Albuminuria; beta 2-Microglobulin; Biomarkers; Chemokine CCL2; Comorbidity; Endothelin-1; Endothelium; Female; Humans; Hypertension; Hyperuricemia; Male; Metabolic Diseases; Middle Aged; Nephritis, Interstitial; Renal Insufficiency; Risk Factors; Uric Acid

An increase in serum uric acid (UA) occurs during the early and middle stages of chronic kidney disease (CKD) and aggravates the deterioration of kidney function. This study aims to explore the relation between UA and endothelial dysfunction in early CKD and its mechanisms in a murine model.. The experimental animals were randomly divided into three groups (n = 10): sham-operation group (control group), right nephrectomy only group (CKD group) and right nephrectomy with oxonic potassium group (CKD with hyperuricemia group). Furthermore, we analyzed the relation between UA and endothelial dysfunction indices in early CKD as well as its mechanisms.. Linear regression analysis showed that the level of serum UA had a significant positive correlation with serum endothelin-1 and the percentage of collagen I positive area, but a negative correlation with serum nitric oxide (NO) and NO/endothelin-1 ratio. In addition, the level of serum UA had significant positive correlations with serum malonaldehyde, serum C-reactive protein, serum oxidatively-modified low-density lipoprotein and serum low-density lipoprotein, but a negative correlation with serum superoxide dismutase.. Endothelial dysfunction in the CKD group was significant and had a positive correlation with the level of serum UA. Endothelial dysfunction in early CKD with hyperuricemia is perhaps related to oxidative stress, micro-inflammation and lipid oxidation.

Topics: Animals; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hyperuricemia; Lipoproteins, LDL; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Superoxide Dismutase; Uric Acid

Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.

Topics: Allopurinol; Analysis of Variance; Animals; Antioxidants; Atrasentan; Biomarkers; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gout Suppressants; Hypertrophy, Left Ventricular; Hyperuricemia; Isoprostanes; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides; Time Factors; Up-Regulation; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

The association between hyperuricemia and cardiovascular diseases has long been recognized. Elevated levels of uric acid may have a causal role in hypertension and cardiovascular diseases. However, the direct effect of uric acid on cardiac cells remains unclear. Therefore, this study was aimed to examine the effect of uric acid in rat cardiac fibroblasts and to identify the putative underlying signaling pathways.. Cultured rat cardiac fibroblasts were stimulated with uric acid; cell proliferation and endothelin-1 (ET-1) gene expression were examined. The effect of uric acid on NADPH oxidase activity, reactive oxygen species (ROS) formation, and extracellular signal-regulated kinases (ERK) phosphorylation were tested to elucidate the intracellular mechanism of uric acid in ET-1 gene expression.. Uric acid-increased cell proliferation and ET-1 gene expression. Uric acid also increased NADPH oxidase activity, ROS formation, ERK phosphorylation, and activator protein-1 (AP-1)-mediated reporter activity. Antioxidants suppressed uric acid-induced ET-1 gene expression, and ERK phosphorylation, and AP-1 reporter activities. Mutational analysis of the ET-1 gene promoter showed that AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression.. These results suggest that uric acid-induced ET-1 gene expression, partially by the activation of ERK pathway via ROS generation in cardiac fibroblasts.

Topics: Animals; Antioxidants; Cell Division; Cells, Cultured; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression; Heart Diseases; Hyperuricemia; MAP Kinase Signaling System; Myocardium; NADPH Oxidases; Phosphorylation; Promoter Regions, Genetic; Rats; Reactive Oxygen Species; Transcription Factor AP-1; Uric Acid

The aim of the study was to investigate endothelial function in patients with arterial hypertension and impaired uric acid metabolism in comparison with patients having arterial hypertension and normal uric acid metabolism. 46 patients aged 32-56 yr with grade I-II AH were included in the study. A group of 36 patients (27 male, 9 female) presented with AH and impaired uric acid metabolism (hyperuricemia), the control group included 10 patients with AH and unaffected uric acid metabolism. Inclusion criteria in the two groups were identical. Endothelial dysfunction was documented in all patients and confirmed by increased levels of serum endothelin-1 and microalbuminuria, qualitative and quantitative changes in the intima-media complex and its thickening. These changes were much more pronounced in patients with hyperuricemia It is concluded that impaired uric acid metabolism in patients with AH leads to rapid onset and progression of endothelial dysfunction. This fact should be taken into consideration by doctors practicing antihypertensive treatment and for the evaluation of cardiovascular risks.

Topics: Adult; Albuminuria; Antihypertensive Agents; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Hyperuricemia; Male; Middle Aged; Risk Factors; Tunica Intima; Uric Acid

Urate, a naturally-occurring antioxidant, is a marker/factor for cardiovascular disease. Hyperuricaemia is associated with IR, MetS and endothelial dysfunction. We characterised the associations between neurohormones, uricaemia, and glucose homeostasis in type 2 diabetes mellitus (T2DM) males. Cross-sectional; 705 T2DM males divided into two groups: uric acid < 7.0 mg/dl (normouricaemic; n=476) versus uric acid >or= 7.0 mg/dl (hyperuricaemic; n=229). HOMA beta-cell function (B), insulin sensitivity (S), hyperbolic product (BxS), and (BxS) loss rate were determined alongside neurohormones (Nt-proANP, BNP, Big ET-1 and UII). Mean age and diabetes duration were not different between groups. Hyperuricaemics had more macroangiopathy, total/central adiposity, IR, hypertension, dyslipidemia and MetS prevalence. Nt-proANP and BNP levels were more than twice as high in hyperuricaemics, whereas Big ET-1 and UII were higher by 46% and 14%, respectively. HOMA (BxS) was higher in hyperuricaemics: 31 (16)% vs. 26 (18)% (p=0.0004). BxS loss rate was faster in normouricaemics: 1.36 (0.54)% vs. 1.20 (0.43)%/year(-1) (p<0.0001 ). The proportion with HbA(1C) < 7.0% was 39% (normouricaemics) vs. 49% (hyperuricaemics; p=0.0091). In T2DM males, hyperuricaemia is associated with raised neurohormones together with better beta-cell indices. Urate's dual properties may translate into beneficial (glucose homeostasis) and detrimental (raised neurohormones) effects.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelin-1; Glycated Hemoglobin; Humans; Hyperuricemia; Insulin; Insulin-Secreting Cells; Male; Metabolic Syndrome; Middle Aged; Natriuretic Peptide, Brain; Up-Regulation; Uric Acid

It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats.. In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid.. These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Angiotensins; Animals; Cells, Cultured; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension; Hyperuricemia; KATP Channels; Kidney; Kidney Diseases; Male; Nitric Oxide; Oxonic Acid; Propylamines; Rats; Rats, Sprague-Dawley; Urate Oxidase; Uric Acid; Xanthine Oxidase