endothelin-1 and Diabetic-Nephropathies

Diabetic kidney disease (DKD) is one of the common complications of diabetes mellitus, which usually progresses to end-stage renal disease and causes great damage to the health of patients. Endothelin-1 (ET-1), a molecule closely associated with the progression of DKD, has increased expression in response to high glucose stimulation and is involved in hemodynamic changes, inflammation, glomerular and tubular dysfunction in the kidney, causing an increase in proteinuria and a decrease in glomerular filtration function, ultimately leading to glomerulosclerosis and renal failure. This paper aims to review the molecular level changes, regulatory mechanisms, and mechanisms of action of ET-1 under DKD, clinical trials of ET-1 receptor antagonists in recent years and current problems, to provide basic information and new research directions and ideas for the treatment of DKD and ET-1-related research.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Endothelin-1; Humans; Kidney; Kidney Glomerulus; Podocytes

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Topics: Angiogenesis Inhibitors; Animals; Consensus; Diabetic Nephropathies; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Humans; Hyperhomocysteinemia; Hypertension; Kidney; Kidney Transplantation; Pre-Eclampsia; Pregnancy; Renal Insufficiency, Chronic; Vitamin D

Endothelin-1 (ET-1) is the most potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN). Areas covered: Physiopathological actions of ET-1 on the kidney. Both dual ETAR/ET

Topics: Animals; Atrasentan; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Humans; Proteinuria; Pyrrolidines; Renal Insufficiency, Chronic

Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.

Topics: Animals; Clinical Trials as Topic; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Isoxazoles; Kidney Failure, Chronic; Pyridines; Pyrimidines; Renal Dialysis; Renal Insufficiency, Chronic; Thiophenes; Treatment Outcome

Over the years, a very large amount of evidence has accumulated indicating that endothelin (ET)-1 is an important stimulus for inflammation. This is true for a wide range of organ system diseases, including chronic kidney disease. Nonetheless, our understanding of the role and mechanisms by which ET-1 promotes the activation of both the innate and adaptive immune systems is not understood. ET-1 can directly activate neutrophils as well as endothelial cells to stimulate production of chemoattractant factors, such as monocyte chemoattractant factor-1, and increase synthesis of cell adhesion molecules, such as soluble ICAM-1. The mechanisms that trigger these events, however, are less clear. Elevated blood pressure as well as hyperglycemia could be important factors that facilitate ET-1-dependent inflammation. While renal inflammation has not been used as an endpoint for drug development, the rationale for the use of ET antagonists as anti-inflammatory agents in chronic kidney disease is quite strong, based on animal studies and at least one study in humans with nondiabetic nephritis. While the preponderance of evidence suggests that ET(A) selective antagonists are advantageous over combined ET(A/B) receptor blockers, considerably more work needs to be done in order to understand the complex role of ET in renal inflammation.

Topics: Animals; Diabetic Nephropathies; Endothelin-1; Humans; Hypertension; Nephritis; Receptors, Endothelin

Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.

Topics: Animals; Antihypertensive Agents; Diabetic Nephropathies; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Evidence-Based Medicine; Humans; Kidney Failure, Chronic; Receptors, Endothelin

Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.

Topics: Animals; Biomarkers; Diabetic Nephropathies; Endothelin-1; Endothelins; Humans

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET(A) receptor antagonists are discussed.

Topics: Cardiovascular Agents; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Endothelin Receptor Antagonists; Endothelin-1; Humans; Microcirculation; Receptors, Endothelin; Treatment Outcome; Up-Regulation

Diabetic nephropathy is a microvascular complication of diabetes. Specifically, it represents a major cause of morbidity and mortality in type 1 and type 2 diabetic subjects and has become the leading cause of end-stage renal disease in the Western world. Diabetic nephropathy appears to develop as a result of interactions between environmental insults and genetic susceptibility. Indeed, hyperglycemia is a clinical prerequisite for this complication, but it should be noted that only a subset of diabetic subjects will ultimately develop nephropathy. Over recent decades, cellular and molecular mechanisms underlying diabetic nephropathy have been increasingly delineated. In particular, diabetic kidney disease appears to occur as a result of the deleterious effects of both metabolic and hemodynamic insults, which at the cellular level lead to the activation of intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines and growth factors, which mediate and/or amplify the renal damage. This ultimately leads to the structural and functional features characteristic of diabetic kidney disease. In the present review we summarize the evidence for key mediators of injury, which appear to be excellent treatment targets in diabetic nephropathy. The targets include various vasoactive hormones, the biochemical processes of the advanced glycation and protein kinase C. Furthermore, we review current and potentially new renoprotective therapies in the setting of diabetes.

Topics: Angiotensin II; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Glycation End Products, Advanced; Humans; Hypertension; Protein Kinase C; Urotensins

The global epidemic of diabetes mellitus has led to a continuous increase in the prevalence of diabetic nephropathy over the past years. Thus, diabetic nephropathy is currently the number one cause of end-stage renal disease in the Western world. It represents a major public health problem for which more effective prevention and treatment strategies are needed. Thiazolidinediones (TZDs) are a class of agents that lower blood glucose through reduction of insulin resistance in patients with type 2 diabetes. Growing evidence support the concept that TZDs have several beneficial effects on the cardiovascular system beyond their effects on glycemic control. These benefits include: blood pressure lowering, triglyceride reduction, high-density lipoprotein-cholesterol elevation, and reduction in subclinical vascular inflammation. Moreover, data from several animal and human studies support the notion that TZDs reduce urine albumin excretion and may prevent development of renal injury. The relative lack of evidence, however, demonstrating the effects of TZDs on hard renal outcomes mandates the need for well-designed trials with this particular objective. This paper summarizes all the data from clinical and experimental studies relevant to a possible renoprotective effect of TZDs and discusses actions of these compounds that may contribute toward this effect.

Topics: Albuminuria; Animals; Blood Pressure; Chromans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Humans; Hypoglycemic Agents; Kidney; Kidney Failure, Chronic; Pioglitazone; PPAR gamma; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Factors; Rosiglitazone; Thiazolidinediones; Time Factors; Troglitazone

Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ET(A) and ET(B) receptors, while constrictor effects are primarily transduced by ET(A) receptors, dual ET receptor blockade may be superior over selective ET(A) antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.

Topics: Acute Kidney Injury; Animals; Chronic Disease; Diabetic Nephropathies; Endothelin-1; Endothelins; Glomerulonephritis; Hepatorenal Syndrome; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Receptors, Endothelin

Endothelin is a vasoconstrictor and a mitogenic peptide. It is able in vivo as well as in vitro to affect renal function and structure. Experiments conducted on animal models have shown that diabetes mellitus is associated with an increase in urinary and plasma endothelin levels. This increase, is probably correlated to renal damage progression and to characteristic alterations in diabetic nephropathy. Also studies conducted on diabetic patients have demonstrated an increase in plasma endothelin. The role of endothelin should therefore be considered because it could be involved in the pathogenesis of diabetic nephropathy.

Topics: Animals; Diabetic Nephropathies; Endothelin-1; Humans

Topics: Animals; Diabetic Nephropathies; Endothelin-1; Humans; Kidney Failure, Chronic; Reactive Oxygen Species

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Hemodynamics; Humans; Kidney Failure, Chronic; Metalloendopeptidases; Renin-Angiotensin System

Topics: Animals; Diabetic Nephropathies; Disease Progression; Endothelin-1; Humans; Proteinuria

This study aims to investigate the effect of hyperbaric oxygen combined with alprostadil in the treatment of elderly diabetic nephropathy (DN) and its effect on serum miR-126 and miR-342 levels. The total effective rate of the study group was 91.53% after treatment, which was higher than that (74.58%) of the control group (p<0.05); the levels of UAER, Scr, BUN and HbA1c, FPG, 2h PG were lowered in the two groups after treatment, and the levels of these indexes were lower in the study group than those in the control group (p<0.05); the levels of vWF, ET-1, CD8+, miR-342 were lowered after treatment for the two groups, and the levels of these indexes were lower in the study group than those in the control group; the levels of NO, CD3+, CD4+ and miR-126 were increased after treatment and the levels were higher in the study group than those in the control group (p<0.05). The application of hyperbaric oxygen combined with alprostadil in the treatment of elderly DN patients can improve renal function, lower blood glucose, improve vascular endothelial function and immune function, adjust serum miR-126 and miR-342 levels, thereby increasing curative effect.

Topics: Aged; Aged, 80 and over; Alprostadil; Blood Glucose; Blood Urea Nitrogen; CD8 Antigens; Creatinine; Diabetes Mellitus; Diabetic Nephropathies; Endothelin-1; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Hyperbaric Oxygenation; Male; MicroRNAs; Middle Aged; Treatment Outcome; Vasodilator Agents; von Willebrand Factor

The aim of study was the optimization of treatment in patients with arterial hypertension and coexistent type 2 diabetes mellitus. The study involved 96 persons with arterial hypertension and type 2 diabetes mellitus (2 of them were excluded). Patients with arterial hypertension and type 2 diabetes mellitus (n=94) were divided in two subgroups: persons from the first (n=54) were treated by telmisartan 40-80 mg/day; second (n=40) - by lisinopril 10-20 mg/day. People from the first subgroup (n=54) were divided in Іa (n=25) and Іb (n=29) according to the level of endothelin-1. Persons from the Іa subgroup with less than 10 pg/ml levels of endothelin were treated by telmisartan 40 mg/day. People from the Іb subgroup with more than 10 pg/ml levels of endothelin were treated by telmisartan 80 mg/day. Patients were observed by echocardiography, albumin excretion rate in six months and by glycated hemoglobin in 3 months. Telmisartan is not worse than lisinopril according to protection of heart and kidney. Under the influence of treatment with telmisartan at a dose of 40 mg/day in subjects with arterial hypertension and type 2 diabetes mellitus and less than 10 pg/ml level of endothelin-1, the values of albumin excretion rate decreased by 9,7% (p=0,0328), and left ventricular mass index - by 6,7% (p=0,0007). In coexistent patients with greater than 10 pg/ml level of endothelin-1 and 80 mg/day dose of telmisartan, the level of albumin excretion rate was reduced by 4,9% (p=0,0435), and left ventricular mass index - by 3,1% (p<0,0001). If the level of this indicator is less than 10 pg/ml, the dose of telmisartan is 40 mg/day, if the level of endothelin-1 is more than 10 pg/ml, the dose of telmisartan is 80 mg/day.

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Glycated Hemoglobin; Humans; Hypertension; Lisinopril; Middle Aged; Renin-Angiotensin System; Telmisartan; Treatment Outcome

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrasentan; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Endothelin-1; Female; Humans; Kidney Function Tests; Lipids; Male; Middle Aged; Pyrrolidines

To investigate the effects and mechanisms of sodium ferutate (SF) in treating diabetic nephropathy (DN).. Eighty patients of diabetes mellitus type 2 with DN were randomly divided into two groups, 40 cases in each group. The routine group treated with conventional treatment including dietary therapy and hypodermic injection of insulin, and the SF group treated with intravenous dripping of SF 300 mg/d additionally besides the conventional therapy, the therapeutic course for both groups was 4 weeks. And 40 healthy volunteers were allocated in a group for normal control. Before and after therapy, levels of fasting blood glucose (FBG), hemoglobin A1c(HbA1c), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C), serum creatinine (SCr), blood urea nitrogen (BUN), mean arterial pressure (MAP), urinary albumin excretion rate (UAER), serum collagen type IV (CIV) and endothelin (ET) were detected.. After 4 weeks of treatment, FBG and HbA1c reduced obviously in both groups with insignificant difference in comparison of them (P > 0.05). Before treatment, TG, TC, MAP, SCr, BUN, UAER, CIV and ET were markedly higher in DN patients than those in the health control (P < 0.05), these criteria decreased significantly in the SF group (P < 0.05) but insignificantly in the routine group (P > 0.05) after treatment, showing difference between the two groups (P < 0.05).. Sodium ferulate could ameliorate lipid metabolic disorder, reduce blood pressure, lower UAER and CIV level, and improve renal function in DN patients, the mechanism might be through decreasing ET production and inhibiting the combining of ET with its receptor.

Topics: Adult; Coumaric Acids; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Insulin; Ligusticum; Male; Middle Aged; Phytotherapy

In order to explore the therapeutic effect of tongxinluo capsule (TXLC) on diabetic nephropathy, the influence on plasma endothelin (ET-1) level of the drug was observed.. All the 63 patients enrolled were randomly divided into the treatment group and control group. They were all treated with low protein diabetic diet, oral administration of hypoglycemic or injection of insulin, calcium antagonist according to level of blood pressure and supportive symptomatic treatment. To the treated group, 2 capsules of TXLC were given additionally three times a day. The efficacy was evaluated after 8 weeks' treatment. The chief indices observed before and after treatment were endogenous creatinine clearance rate (CCr), urinary albumin excretion rate (UAER), urinary beta2-microglobulin (beta2-MG), fasting blood-glucose (FBG) and ET-1.. Before treatment, no significant difference was shown in all the tested indices between the treated group and the control group. After treatment, levels of CCr, UAER, beta2-MG, ET-1 and FBG significantly changed in the treated group, showing significant difference as compared with those before treatment (P < 0.05). Moreover, comparison of these indices in the two groups after treatment, excepting FBG, also showed statistical significance (P < 0.01).. TXLC shows obvious effect in reducing plasma ET-1 and UAER, it is definitely effective in repairing the renal tubular interstitial damage, and effectively delay the progress of diabetic nephropathy, improve the renal function, and is favorable to ameliorate hyperglycemia auxiliarily.

Topics: Albuminuria; Capsules; Diabetic Nephropathies; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Male; Phytotherapy

To study the therapeutic effect of Astragalus injection (AI) in treating early stage diabetic nephropathy (DN) patients.. The total of 136 early diabetic nephropathy patients were randomly divided into two groups, 50 cases in the conventional treated group and 86 in the AI treated group, the therapeutic course being 3 weeks. Levels of plasma endothelin-1 (ET-1), 24 hrs urinary albumin excretion rate (uAER), and platelet granule membrane protein (GMP-140), 6-keto-prostaglandin F1 alpha(6-keto-PGF1 alpha), and thromboxane B2(TXB2) before and after treatment were determined by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) respectively. Moreover, the above-mentioned criteria in 26 healthy subjects were also measured for control.. The plasma ET-1, GMP-140, TXB2 and uAER levels in DN patients were higher, but 6-keto-PGF1 alpha level was lower than those in healthy subjects. The above elevated criteria in DN patients could be lowered by AI treatment.. The pathogenesis and development of DN might be closely associated with the changes of plasma ET-1 level and platelet function. Astragalus could improve the above-mentioned changes in patients of early stage DN.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Astragalus propinquus; Diabetic Nephropathies; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Infusions, Intravenous; Male; Middle Aged; P-Selectin; Phytotherapy; Platelet Activation; Thromboxane B2

A high blood concentration of endothelin (ET)-1 may participate in the onset and progress of diabetic microangiopathy, resulting in neuropathy. We examined the therapeutic effects of prostaglandin E1 (PGE1), which possesses both a peripheral vasodilating action and inhibition of platelet aggregation, on diabetic microangiopathy. Increases in both skin temperature and peripheral never conduction velocity in diabetic patients were recorded four weeks after Lipo PGE1 administration. A quantitative decrease in urinary albumin concentration was also observed, suggesting its efficacy of action was on diabetic nephropathy. Lipo PGE1 administration reduced the elevated circulating plasma ET-1 levels in the diabetic patients. As an increase in ET-1 concentrations is thought to correlate with the onset and progress of diabetic microangiopathy, the reduction of plasma ET-1 concentration by Lipo PGE1 administration may be one reason for the improvement in diabetic neuropathy and nephropathy.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Alprostadil; Angiotensins; Blood Glucose; Collagen Type IV; Cyclic AMP; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electric Conductivity; Electrocardiography; Endothelin-1; Fasting; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Peripheral Nerves; Renin; Skin Temperature

Transforming growth factor-β1 (TGF-β1), endothelin-1 and angiotensin II are responsible for extracellular matrix accumulation within the kidney in diabetic nephropathy.. This study evaluated the effect of adding Gum Arabic (GA) and insulin on serum glucose, renal function, TGF-β1, endothelin-1, and angiotensin II in rats with diabetic nephropathy.. Sixty male Sprague-Dawley rats were divided into; normal, normal plus GA, diabetic rats (DM), DM plus insulin, DM plus GA, and DM plus insulin plus GA groups. Levels of glucose and creatinine in serum, TGF-β1, angiotensin II, and endothelin-1 in renal homogenate and HbA1c were measured.. Serum creatinine, TGF-β1, angiotensin II, and endothelin-1 were increased in diabetic rats. GA decreased serum glucose, TGF-β1, angiotensin II, endothelin-1, and HbA1c in diabetic rats. GA and insulin decreased serum glucose, creatinine, TGF-β1, angiotensin II, endothelin-1, and HbA1c in diabetic rats.. Co-administration of GA with insulin to rats with diabetic nephropathy improved the glycemic state, renal function, TGF-β1, endothelin-1, and angiotensin II.

Topics: Acacia; Angiotensin II; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Glucose; Glycated Hemoglobin; Gum Arabic; Insulins; Kidney; Male; Rats; Rats, Sprague-Dawley; Senegal; Transforming Growth Factor beta1

Topics: Albuminuria; Atrasentan; Diabetes Mellitus; Diabetic Nephropathies; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Humans; Pyrrolidines

Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemokines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.

Topics: Adipokines; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Non-alcoholic Fatty Liver Disease; Obesity; Receptor, Endothelin A; Vasoconstriction

To investigate the therapeutic mechanisms underlying prostaglandin E1 (PGE1) and angiotensin-converting enzyme inhibitor (ACEI) on reducing urinary protein in diabetic kidney disease (DKD). DKD rats were established and randomly divided into four groups: PGE1 (10 μg/kg/day) (P group), ACEI (10 mg/kg/day) (A group), combination of PGE1 with ACEI treatment (P + A group), and saline treatment group (DKD group). Untreated rats were used as normal control (N group). Urinary albumin, endothelin-1 (ET-1), angiotensin II (AngII), TUNEL assay, Masson's trichrome staining, and immunohistochemistry staining for CD68 were evaluated in all groups. Ten days after treatment, urinary albumin was significantly decreased in the P and P + A groups (p < 0.01 vs. the DKD group). At the end of 8 weeks, the albumin was still significantly reduced in the P + A group (p < 0.05 vs. the A group). ET-1 and AngII were also significantly decreased in three treatment groups (p < 0.01 vs. the DKD group), especially in the P + A group. Few cells underwent apoptosis in glomerular regions in DKD rats, while amounts of apoptotic cells were seen in tubules regions. Further, apoptosis and the areas of fibrosis in tubulointerstitial were both decreased most in the P + A group compared with the DKD group. Apoptosis of renal tubular epithelial cells may participate in the development and progression of DKD in rats. Combination of PGE1 with AGEI remarkably protects renal function compared with PGE1 or ACEI monotherapy. The potential therapeutic mechanisms of PGE1 and AGEI might be via multiple targets and, at least in part, through inhibiting the apoptosis of renal tubular epithelial cells.

Topics: Alprostadil; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Endothelin-1; Epithelial Cells; Kidney Tubules; Macrophages; Male; Nephritis, Interstitial; Rats, Wistar

Diabetic nephropathy (DN) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Several lines of evidence implicate the endothelin (ET) system in the pathophysiology of DN. The aim of the present study was to analyze if genetic polymorphisms of the ET-1 (EDN1) gene affect susceptibility to DN in Caucasians with T2DM.. The study population consisted of 651 Caucasian subjects with T2DM of more than 10 years' duration: 276 patients with DN (cases) and 375 patients without evidence of DN (controls). Polymorphisms in ET-1 (EDN1) gene, rs5370, rs1476046, and rs3087459, were studied.. Genotype distributions of the studied polymorphisms showed no significant difference between cases and controls.. We provide evidence that the rs5370, rs1476046, and rs3087459 polymorphisms of EDN1 gene are not risk factors for DN in Caucasians with T2DM.

Topics: Adult; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Genetic; Reference Values; Retrospective Studies; Risk Assessment; Sensitivity and Specificity; White People

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1-Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Animals; Antioxidants; Chromatography, High Pressure Liquid; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Susceptibility; DNA, Mitochondrial; Endothelin-1; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Kidney Glomerulus; Male; Mesangial Cells; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Organophosphorus Compounds; Oxygen Consumption; Piperidines; Podocytes; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Signal Transduction; Young Adult

Objective Endothelial dysfunction (ED) plays an important role in the pathogenesis of diabetic nephropathy. The purpose of the study was to determine flow mediated endothelial dependent vasodilatation (FMD) measurements and serum soluble (s) endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) levels in patients with type 1 diabetes mellitus (T1DM) with or without increased urinary albumin excretion (UAE) and compare them with the healthy controls. Subjects and methods Seventy three patients with T1DM were enrolled. Patients were divided into two subgroups according to microalbumin measurements in 24-hr urine collections. The diabetic patients without microalbuminuria (41 patients) were defined as Group I and those with microalbuminuria (32 patients) were defined as group II. A hundred age and sex matched healthy subjects participated as the control group (Group III). Serum sET-1, sICAM-1, sVCAM-1 levels and FMD measurements were determined in all participants. Results Median FMD measurement was significantly lower in the diabetic groups compared with the control group (6.6, 6.4 and 7.8% in Group I, II and III, respectively) (p < 0.05). FMD was negatively correlated with age (p = 0.042). Median serum sICAM-1 level was higher in the patient groups compared to the control group (p < 0.05). Median serum sVCAM-1 level was higher in the group of patients with increased albuminuria compared to the normoalbuinuric and the control group (p < 0.05). Serum sVCAM-1 level was found to be positively correlated with degree of urinary albumin excretion (p < 0.001). Conclusion We assume that sVCAM-1 may be used as a predictive marker for risk stratification for nephropathy development and progression.

Topics: Adult; Albuminuria; Analysis of Variance; Biomarkers; Blood Flow Velocity; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Male; Predictive Value of Tests; Reference Values; Risk Factors; Statistics, Nonparametric; Vascular Cell Adhesion Molecule-1; Vasodilation

Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN.

Topics: Animals; Diabetic Nephropathies; Endothelin-1; Glucuronidase; Glycocalyx; Kidney Glomerulus; Male; Mice; Podocytes; Proteinuria

Glycemic variability (GV) creates challenges to glycemic control and may be an independent marker for unfavorable outcome in management of patients with diabetes. This study was designed to investigate the effect of excessive visit-to-visit GV on the progression of endothelial and renal dysfunction in patients with type 2 diabetes mellitus (T2DM).. Two hundred and thirty nine patients with T2DM, who were recruited from outpatient, completed 48-month follow-up visit. Visit-to-visit GV was calculated by the standard deviation (SD) and coefficient of variation (CV) of serially measured HbA1c and fasting plasma glucose (FPG). Endothelial and renal function was assessed at baseline and end of follow-up.. At end of follow-up, brachial flow-mediated dilation (FMD), nitric oxide (NO), creatinine-based estimated glomeruar filtration rate (eGFR-Cr), and cystatin C-based estimated glomeruar filtration rate (eGFR-Cys C) increased, and endothelin-1 and urine albumin/creatinine ratio (ACR) declined as compared with baseline in overall (P < 0.05). The increment of FMD, NO, eGFR-Cr, and eGFR-Cys C and the decrement of endothelin-1 and ACR in first tertile group were significantly greater than those in third tertile group classified by tertile of either SD of HbA1c or SD of FPG. Change percentage of FMD, NO, eGFR-Cr, and eGFR-Cys C were positively, and change percentage of endothelin-1 and ACR were negatively correlated with SDs of HbA1c and FPG, and CVs of HbA1c FPG (P < 0.01, respectively). After adjusted for mean HbA1c, mean FPG, baseline demographic, and clinical characteristics, SD of HbA1c and SD of FPG were always statistically correlated with change percentage of FMD, NO, endothelin-1, ACR, eGFR-Cr, and eGFR-Cys C.. Excessive visit-to-visit GV independently deteriorates the progression of endothelial and renal dysfunction in patients with T2DM.

Topics: Aged; Albuminuria; Creatinine; Cystatin C; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium; Fasting; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney; Male; Middle Aged; Nitric Oxide; Office Visits; Vasodilation

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Glycocalyx; Humans; Proteinuria

Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy.. We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m(2); n = 50), group II (GFR ≥ 60 mL/min/1.73 m(2), n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured.. There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = -0.52, p < 0.001), ERPF (r = -0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR.. A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.

Topics: Adult; Aged; Cross-Sectional Studies; Diabetic Nephropathies; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Plasma Flow, Effective

The pathogenesis of interstitial fibrosis in diabetic nephropathy (DN) is an intractable problem without good therapy. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) is an important mechanism for tubular epithelial cells undergoing profibrotic change in DN. Endothelin-1 (ET-1) is an important cytokine which can cause fibrogenesis and is reportedly involved in DN. However, the role of ET-1 in EMT in DN is unknown. The present study was designed to investigate the role of ET-1 in high glucose-induced EMT and the signaling pathway mediating the effect of ET-1 in renal tubular cells.. Tubular epithelial cells (NRK52E) were treated with normal glucose (d-glucose 5.6mmol/L, NG), high glucose (30mmol/L, HG), high osmotic (d-glucose 5.6mmol/L+d-mannitol 24.4mmol/L), HG+ETA antagonist BQ123 (2μg/ml), ET-1, ET-1+ hypoxia inducible factor (HIF)-1α siRNA, CoCl2 (100μmol/L), CoCl2+HIF-1α siRNA or CoCl2+BQ123. The supernatant level of ET-1 was measured by ELISA and the expression of vimentin, E-cadherin and HIF-1α was detected by RT-PCR and western blot.. The ET-1 level increased markedly in the supernatant of NRK52E incubated with HG. In NRK52E induced with HG or ET-1, the expression of vimentin was upregulated, whereas the expression of E-cadherin was downregulated. BQ123 attenuated HG- and CoCl2-induced EMT while HIF-1α siRNA did not affect ET-1 induced EMT.. High glucose induced ET-1 production that mediated the EMT induced by high glucose in renal tubular epithelial cells, and HIF-1α acted as the upstream signal to regulate ET-1.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Glucose; Immunoblotting; Kidney Tubules; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction

The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity an

Topics: Adiposity; Animals; Atrial Natriuretic Factor; Blood Glucose; Chemokine CCL3; Diabetic Nephropathies; Dinoprost; Endothelin-1; Extracellular Matrix Proteins; Heme Oxygenase (Decyclizing); Hemin; Inflammation; Interleukins; Kidney; Macrophages; Male; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).. In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.. Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.. Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.

Topics: Aged; Albuminuria; Blood Glucose; Blood Pressure; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Endothelin-1; Female; Glomerular Filtration Rate; Glucuronidase; Glycated Hemoglobin; Humans; Klotho Proteins; Lipids; Male; Middle Aged; Oxidative Stress; Protein Precursors; Superoxide Dismutase

The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.

Topics: Animals; beta Catenin; Diabetic Nephropathies; Down-Regulation; Endothelin-1; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Podocytes; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction

Topics: Animals; Cardiovascular Diseases; Cholesterol, HDL; Diabetic Nephropathies; Endothelin-1; Female; Humans; Male; Podocytes; Renal Insufficiency, Chronic

The objective of this study was to detect the expression of Angiotensin-II (Ang-II), Hypoxia-inducible factor-1α (HIF-1α) and Endothelin-1 (ET-1) in the kidneys of patients with diabetic nephropathy (DN) and to investigate their relationship with renal interstitial fibrosis (RIF). A total of 47 paraffin specimens of patients with DN and six controls were enrolled in this study, and all were diagnosed by histopathology. We studied the expressions of Ang-II, HIF-1α and ET-1 by immuno-histochemical staining and the level of RIF by Masson staining. The following results were found: (a) RIF existed in the kidneys of patients with DN, (b) the expressions of Ang-II, HIF-1α and ET-1 were lower in the control group but increased significantly in the DN group, (c) the expression of Ang-II, HIF-1α and ET-1 in tubular epithelial cells directly correlated with RIF (r s = 0.659, 0.633, 0.716, P <0.01) and (d) the expression of Ang-II, ET-1 and HIF-1α in the kidneys of patients with DN positively correlated with serum creatinine (Scr) levels (r s = 0.391, 0.594, 0.531, P <0.01) but they did not correlate with the 24-h urinary protein, blood glucose and serum albumin levels. These results provide new insights suggesting that over-expression of Ang-II, HIF-1α and ET-1 promote the progression of RIF in DN. Thus, targeting reduction in the expression of Ang-II, HIF-1α and ET-1 can delay RIF in DN. Further studies are needed to validate this observation.

Topics: Adult; Aged; Angiotensin II; Diabetic Nephropathies; Disease Progression; Endothelin-1; Female; Fibrosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Male; Middle Aged; Nephritis, Interstitial

We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-β, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-β-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.

Topics: Acute-Phase Proteins; Adult; Animals; Biomarkers; Case-Control Studies; Chemokine CCL2; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Female; Glomerular Filtration Rate; Growth Differentiation Factor 15; Humans; Immunoassay; Interleukin-6; Kidney; Lipocalin-2; Lipocalins; Male; Mice; Middle Aged; Pilot Projects; Proto-Oncogene Proteins; Transcriptome; Transforming Growth Factor beta

Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria.. This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria.. Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR.. In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.

Topics: Adult; Biomarkers; Biopsy; Cross-Sectional Studies; Diabetic Nephropathies; Disease Progression; Endothelin-1; Female; Follow-Up Studies; Humans; Immunohistochemistry; Kidney; Male; Middle Aged; Receptor, Endothelin A; Retrospective Studies

To investigate the effect of angiotensin II AT1 receptor blocker valsartan on hypoxia-inducible factor (HIF)-1α-mediated gene activation and its association with renal interstitial fibrosis (RIF) in diabetic nephropathy rats.. Sprague-Dawley rats were randomly divided into 3 groups: control (C group), streptozocin-induced diabetic nephropathy (D group), and valsartan-treated D rats (T group). At end of the 4th, 8th and 12th week 6 rats from each group were sacrificed and blood, urine and kidneys were collected. Blood glucose, serum creatinine (Scr) and 24-h urinary protein were measured and kidneys were processed for Masson-stain as well as immunohistochemistry and real time-PCR analyses of the expressions of HIF-1α, and its target genes tissue inhibitor of metalloproteinase (TIMP)-1 and endothelin (ET)-1 in the kidney.. (1) At the 4th, 8th and 12th week, the areas of RIF were significantly increased in D and T groups, which was accompanied by higher levels of 24-h urinary protein, Scr, HIF-1α, ET-1 and TIMP-1 compared with C group. (2) At the 8th and 12th week, the above changes were significantly attenuated in T group compared with D group.. Valsartan may reduce HIF-1α-mediated gene activation and consequently improve kidney damage in diabetic nephropathy rats.

Topics: Animals; Blood Glucose; Blotting, Western; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Gene Expression; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Male; Nephritis, Interstitial; Proteinuria; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Streptozocin; Tetrazoles; Tissue Inhibitor of Metalloproteinase-1; Valine; Valsartan

Diabetic nephropathy is a complication of diabetes mellitus leading to end-stage renal disease. Oxidative stress and inflammation play a major role in the pathogenesis of diabetic nephropathy. Green tea, known for its antioxidant and anti-inflammatory properties, has been shown to be renoprotective. We hypothesized that (+)-catechin (CTN), a component of green tea, is responsible for the renoprotection. Our investigation of the therapeutic potential of CTN in streptozotocin-induced diabetic rats demonstrated for the first time that the effects of CTN treatment were comparable with the effects of an angiotensin-converting enzyme inhibitor (ACEi) enalapril for the treatment of albumin excretion. After 12 weeks of CTN treatment with 35 mg/d in the drinking water, urinary albumin excretion and plasma creatinine concentrations in all the diabetic treatment groups were reduced, compared with the diabetic group with no treatment. Urine creatinine and creatinine clearance were higher in diabetic groups treated with CTN and ACEi compared with the diabetic group with no treatment. Endothelin 1, lipid peroxidation, concentration of alanine transferase enzyme, and expression of fibronectin were lower in all the treatment groups compared with the diabetic group with no treatment. Concentrations of free thiols were higher in the CTN-treated group compared with the diabetic rats with no treatment. Our findings suggest that CTN has renoprotective properties comparable with ACEi, and coadministration of CTN and enalapril might be useful in reducing albumin excretion as well as improving endothelial function. (+)-Catechin might be successfully used in the future for clinical situations where ACEi is poorly tolerated or contraindicated.

Topics: Alanine Transaminase; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Camellia sinensis; Catechin; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Endothelin-1; Fibronectins; Lipid Peroxidation; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds

The molecular mechanism linking aldosterone and endothelin-1 in the development of diabetic nephropathy has not been completely elucidated. Here, we provide evidence showing that streptozotocin-induced diabetic rats have significantly increased aldosterone and endothelin-1 in the kidney tissue and markedly decreased expression of Dot1a and Af9. Blocking aldosterone with spironolactone significantly reduced proteinuria, glomerulosclerosis, tubulointerstitial injury and endothelin-1 expression, and significantly increased Dot1a and Af9 expression. Increasing Dot1a and Af9 expression by spironolactone or by stable transfection led to impaired endothelin-1 expression in NRK-52 cells. In contrast, downregulation of Dot1a and Af9 by aldosterone in NRK-52E cells caused upregulation of endothelin-1. Genetic inactivation of Dot1l, which encodes Dot1a, in Aqp2-expressing principal cells of mouse kidney impaired association of Dot1a and H3 dimethyl K79 with the specific subregions of endothelin-1 promoter, and upregulates endothelin-1 mRNA and protein expression. Our data suggest that Dot1a and Af9 repress endothelin-1 in vitro and in vivo. Excessive aldosterone induces kidney injury, in part possibly by downregulating Dot1a and Af9, and thus relieving Dot1a-Af9-mediated repression to increase endothelin-1 transcription. Spironolactone ameliorates kidney injury in Streptozotocin-induced diabetic rats, possibly by restoring Dot1a-Af9-mediated repression to reduce endothelin-1 expression. Therefore, Dot1a and Af9 as aldosterone-downregulated targets are negative regulators of endothelin-1 transcription in vitro and in vivo, and may be considered as new potential therapeutic targets of kidney injury in diabetes.

Topics: Acute Kidney Injury; Aldosterone; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Down-Regulation; Endothelin-1; Histone-Lysine N-Methyltransferase; Humans; Methyltransferases; Mice; Nuclear Proteins; Promoter Regions, Genetic; Rats; Spironolactone; Streptozocin; Up-Regulation

The article deals with studying the degree of increase of the von Willebrand factor and the concentration of endothelin-1 in blood plasma in the subgroups of patients with diabetes mellitus formed depending on of type of disease and presence of phenotype with affection of kidneys. The sampling of 176 patients with diabetes mellitus (65 patients with diabetes mellitus type 1, 111 patients with diabetes mellitus type II) was examined. The control group consisted of 30 healthy persons. In the capacity of biochemical markers of endothelium dysfunction the activity of the von Willebrand factor and the concentration of endothelin-1 in blood were considered. In all patients with diabetes mellitus the biochemical characteristics of endothelium dysfunction are present manifesting by increase of concentration of endothelin-1 in blood which is especially expressed under disease phenotype with affection of kidneys. Despite of the apparent lesion of endothelium in patients with diabetes mellitus compromised with diabetic nephropathy the thrombocytes aggregation induced by ristomicine does not undergo natural changes. Hence, to consider in these patients the increasing activity of the von Willebrand factor as a reliable marker of endothelium dysfunction is not seemed possible.

Topics: Adult; Aged; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Platelet Aggregation; von Willebrand Factor

Diabetic nephropathy (DN) due to microvascular complication is a serious status characterized by continuously progressive until occurrence of the end stage of renal disease. It is attractive to investigate further mechanisms underlying the entity of DN and new drug discovery. We hypothesized that the entity of DN is inflammatory and is characterized by upregulated inflammatory/pro-inflammatory factors such as peroxisome proliferator-activated receptor alpha, NADPH oxidase, endoplasmic reticulum stress (ER stress), and endothelin receptor A (ET(A)) and downregulated connexin 43 (Cx43) in the kidney. Aminoguanidine is a special blocker to advanced glycation end products and argirein, a new compound contains a molecule of rhein linked to L: -arginine by a hydrogen bond. Rhein possesses anti-inflammatory activity and has been chemically modified to produce a new compound diacerein launched in European market for treating osteoarthritis. Argirein with two active molecules rhein and L: -arginine may be effective in suppressing the inflammatory cytokines contributing to the pathogenesis of DN. With a single injection of streptozotocin 65 mg/kg, ip in rats, early diabetic nephropathy was produced and revealed as an increased microalbuminuria, elevated creatinine and urea in serum, associated with upregulation of mRNA and protein of NADPH oxidase p22phox, p47phox, and p67phox and ET(A), upregulated PKR-like eukaryotic initiation factor 2α kinase (PERK), and downregulated Cx43 in the renal tissue. Upregulation of PERK suggested that there is an ER stress involved in the diabetic kidney, along with an increase in inflammatory/pro-inflammatory factors indicating an entity of chronic inflammation. Abnormalities of biomarkers were blunted by either aminoguanidine or argirein significantly. The new compound argirein is potential in alleviating and retarding microvascular complications of diabetes such as DN in clinical settings.

Topics: Animals; Anthraquinones; Aspartic Acid Endopeptidases; Blood Glucose; Blood Urea Nitrogen; Connexin 43; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; eIF-2 Kinase; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Gene Expression; Guanidines; Kidney; Male; Metalloendopeptidases; NADPH Oxidases; Nitric Oxide Donors; PPAR alpha; Protein Subunits; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Diabetic nephropathy is a debilitating disease that leads to end-stage renal failure in the Western world. Hyperglycemia is the initiating factor in several chronic diabetic complications which mediates increased oxidative stress and eventually the increased production of vasoactive factors and extracellular matrix proteins. We hypothesized that curcumin, a potent antioxidant, might be beneficial in preventing the development of diabetic nephropathy because this compound has been shown to inhibit p300, a histone acetyltransferase that plays a role in regulating gene expression through its interaction with the transcription factor nuclear factor-kappaB.. To test this hypothesis, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. These animals were subsequently treated with curcumin for a period of 1 mo.. Real-time reverse transcriptase polymerase chain reaction analyses showed that diabetes-induced upregulation of vasoactive factors (endothelial nitric oxide synthase and endothelin-1), transforming growth factor-beta1 and extracellular matrix proteins (fibronectin and extradomain-B-containing fibronectin) in the kidneys. These changes were associated with increased oxidative stress, mesangial expansion, and p300 and nuclear factor-kappaB activity that were prevented with curcumin treatment.. These beneficial effects of curcumin were mediated through the inhibition of p300 and nuclear factor-kappaB.

Topics: Animals; Antioxidants; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; E1A-Associated p300 Protein; Endothelin-1; Extracellular Matrix Proteins; Kidney; Male; Mesangial Cells; NF-kappa B; Nitric Oxide Synthase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied the association between 43 pathway-related candidate genes with 'intermediate phenotype' (i.e. corresponding plasma protein) and diabetic nephropathy in a customised microarray of 1,536 SNPs.. In this case-control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR) > 113 mg/mmol; the value for controls (n = 503) was ACR < 3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay.. No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing. Therefore, we explored the best approximately 1% SNPs. Of these 13 SNPs, four clustered to a 5' end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04-4.06) (heterozygous) and 2.48 (1.27-4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased oxidative burden. Endothelin-1 SNP (rs1476046G>A, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1 concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96-1.66) and (homozygous) 1.87 (1.13-3.12) (p = 0.0072). Nitric oxide synthase 1 (NOS1) 5' haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26 (0.95-1.67), homozygous 1.57 (1.04-2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases.. Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are needed.

Topics: Aged; Asian People; Blood Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide Synthase Type I; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Singapore

Liuwei Dihuang (Rehmannia complex, RC) decoction, a classic prescription of Traditional Chinese Medicine (TCM), has been used in treating diabetic nephropathy (DN). Among the 6 crude medicines which contains Corni fructus is recognized as the active fraction for its effectiveness. We aimed to investigate, first, if without Corni fructus a modified RC could be still effective, second, if the ethanol extracts could be better than that of water extract and third, the beneficial effect is mainly stemmed from suppressing the endothelin (ET-1) pathway associated with a moderate hypoglycemic effect.. Diabetes for 8 weeks was induced by a single dose of streptozotocin (STZ, 65 mg/kg, i.p.) in rats and treated with RC extracts in either 95%, 70% ethanol or water separately during 5-8th week. The efficacy of extracts was compared with aminoguanidine (AMG).. An increase in albumin and creatinine in 24h urine, blood urea nitrogen (BUN) was found in STZ rats. Oxidative stress was found in renal cortex in association with upregulated plasma ET-1 and mRNA of ETA, decreased MMP 2,9 (matrix matelloproteinases) and increased hydroxyproline.. The RC without Corni fructus was very effective in alleviating DN and ethanol extracts provided greater effects against water extracts. The efficacy in alleviating DN is attributed to normalizing the activated ET system, oxidative stress and MMP 2,9 in combination with a moderate hypoglycemic activity.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drugs, Chinese Herbal; Endothelin-1; Female; Hypoglycemic Agents; Male; Matrix Metalloproteinase 2; Medicine, Chinese Traditional; Nitric Oxide; Phytotherapy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Streptozocin

Plasma endothelin-1 levels rise in diabetes and after exposure to contrast media suggesting a role in progressive diabetic and acute radiocontrast nephropathies. Here we studied individual and combined effects of streptozotocin-induced diabetes and contrast media on renal endothelin converting enzyme-1 levels in the rat. In vivo, medullary (but not cortical) endothelin converting enzyme protein gradually increased 4 to 5-fold following the induction of diabetes or after the administration of contrast media but rose 15-fold when diabetic rats were given contrast media. Changes in mRNA expression paralleled those of the protein. Immunohistochemistry confirmed that increased tubular and endothelial cell endothelin converting enzyme-1 were most pronounced in the medulla. In vitro, endothelin-1 levels increased 3-fold following incubation of endothelial cells with media high in glucose or with contrast and 4-fold with their combination. Endothelin converting enzyme-1 protein and mRNA expression changed in a similar pattern while prepro endothelin-1 mRNA increased with each insult but not in an additive way. Our study shows that diabetes and contrast media up-regulate renal medullary endothelin converting enzyme-1 expression and synthesis.

Topics: Animals; Aspartic Acid Endopeptidases; Contrast Media; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Endothelin-Converting Enzymes; Kidney; Metalloendopeptidases; Rats; RNA, Messenger; Up-Regulation

The pathogenesis of renal hypertension has not yet been fully clarified. As the potential role of endothelin-1 (ET-1) and nitric oxide (NO) has been postulated, their concentrations were determined in plasma and urine of diabetic patients. The study included 30 diabetic patients (both IDDM and NIDDM) with initial or advanced diabetic nephropathy (decreased endogenous creatinine clearance, proteinuria) and 20 healthy control subjects. The correlation with blood pressure and other renal function parameters was monitored and compared with the control group. Also, the effect of ACE inhibitors (ACEI) on ET-1 and NO patterns was monitored in correlation with arterial hypertension. In diabetic patients that did not receive ACEI therapy, the increase in plasma ET-1 was associated with both systolic and diastolic blood pressure elevation, whereas in those administered ACEI the increase in plasma ET-1 was associated with a systolic blood pressure decline. In addition, the increase in plasma NO was accompanied by a statistically significant decline of both systolic and diastolic blood pressure in diabetic patients receiving ACEI.

Topics: Aged; Blood Pressure; Diabetic Nephropathies; Endothelin-1; Female; Humans; Hypertension, Renal; Male; Nitric Oxide

We aimed to investigate the effects of Liuwei Dihuang decoction (LW) on the endothelin-1-reactive oxidative species (ET-ROS) system and matrix metalloproteinases (MMPs) in the early diabetic nephropathy induced by streptozotocin (STZ) in rats. Rats were divided into six groups as follows: the control group, the untreated model group, the treated groups with the LW (5, 10 and 15 g kg(-1), p.o.) and the aminoguanidine-treated group (100 mg kg(-1), orally). The treatment was performed for 4 weeks, beginning on the fifth week after one intraperitoneal injection of STZ (65 mg kg(-1)). In the untreated model group, increased blood glucose, decreased plasma insulin level and an impaired renal function were observed. There was an altered redox system shown by an increased malondialdehyde and decreased activity of glutathione peroxidase and superoxide dismutase in the renal cortex. An enhanced inducible nitric oxide synthetase, total nitric oxide synthase and constitutive nitric oxide synthase and a declined nitric oxide were found. An increased extracellular matrix was indicated by an abnormality of MMP-2 and MMP-9 activities and an increase in hydroxyproline. An up-regulated ET-1 level and increased mRNA expression of endothelin-converting enzyme, preproET-1 and ET( A) receptor were presented in the affected renal cortex, but no change in ET(B) receptor mRNA. The LW was most effective in reversing these changes in diabetic rats and was as effective as aminoguanidine. The benefits of the extracts in relieving the abnormalities in early diabetic nephropathy are likely to be mediated by suppression of the renal ET-ROS system and escalating the activity of MMPs.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Endothelin-1; Enzyme Inhibitors; Female; Gene Expression Regulation; Guanidines; Kidney Cortex; Male; Matrix Metalloproteinases; Phytotherapy; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Streptozocin

The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure.

Topics: Animals; Blood Pressure; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Endothelin-1; Hypertension; Kidney; Kidney Failure, Chronic; Myocardium; Rats; Rats, Mutant Strains; Receptor, Endothelin A; Receptor, Endothelin B

We examined the role of endothelial dysfunction in the development and progression of cardiorenal syndrome in 93 patients with type 1 diabetes mellitus.. According to the stage of renal insufficiency all patients were divided into equal groups: those with normal albumin excretion rate, with microalbuminuria, with proteinuria, and with chronic renal failure. We analyzed endothelial flow-mediated dilation of the brachial artery, levels of endothelin-1, von Willerbrand factor, C-reactive protein, renal:albumin and protein excretion rates, glomerular filtration rate (GFR), and cardiovascular (ECG, echocardiography, blood pressure monitoring) functions.. There were negative correlations between the GFR, BP level and endothelial dysfunction markers. At the same time GFR correlated positively with the coefficient of sensitivity of endothelium to shear stress. There were also positive correlations between BP, permeability of glomerular filter and endothelial dysfunction markers and negative correlation with the coefficient of sensitivity of endothelium to shear stress and GFR. Left ventricle mass correlated with markers of endothelial dysfunction and stage of renal disease. Patients with chronic renal failure had negative correlations between LVM and GFR, ILVM and GFR and a positive correlation between ejection fraction and GFR.. There is a close relationship between endothelial dysfunction and development and progression of renal and cardiovascular pathology in patients with type 1 diabetes mellitus.

Topics: Adolescent; Adult; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Glomerular Filtration Rate; Heart Diseases; Humans; Male; Middle Aged; Ventricular Dysfunction, Left; Ventricular Function, Left

To elucidate the role of endothelial dysfunction in formation of cardiorenal syndrome in patients with type 1 diabetes and diabetic nephropathy.. Sixty patients with type 1 diabetes were divided according to severity of nephropathy into the following groups: with normal albuminuria (n=15), microalbuminuria (n=15), proteinuria (n=15), and chronic renal failure (n=15). Control group consisted of 15 healthy subjects of similar age and sex. Methods of investigation included assessment of brachial artery endothelium dependent dilation by duplex scanning during test with reactive hyperemia, measurement of levels of serum markers of endothelial dysfunction (endothelin-1, von-Willebrand factor), and inflammation (C-reactive protein), analysis of parameters of 24-hour blood pressure monitoring and echocardiography data.. More severe diabetic nephropathy was associated with higher prevalence of cardiac pathology. Frequency of ischemic heart disease was 13 (2/15), 33 (5/15) and 53% (8/15), frequency of left ventricular concentric hypertrophy and remodeling - 33 (5/15), 40 (6/15) and 60% (9/15) among patients with microalbuminuria, proteinuria and chronic renal failure, respectively. Abnormalities of 24-hour blood pressure rhythm as well as signs of endothelial dysfunction were more pronounced in patients with more severe nephropathy. Correlation analysis revealed significant relationships between markers of endothelial dysfunction, parameters of renal function, blood pressure level and mass of left ventricular myocardium.. In patients with type 1 diabetes: endothelial dysfunction represents a link integrating processes of progression of nephropathy and development of cardiovascular pathology; close relationship between these processes constitutes a basis of cardiorenal syndrome; active search for cardiac pathology should be initiated on the stage of microalbuminuria.

Topics: Adolescent; Adult; Biomarkers; Brachial Artery; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Heart Diseases; Humans; Male; Middle Aged; Prognosis; Syndrome; Ultrasonography, Doppler, Duplex; Vasodilation; von Willebrand Factor

To investigate the interrelation between endothelin-1 (ET-1) and angiotensin II (AngII) in kidney tissue of rats with diabetic nephropathy.. Wistar rats were performed a removal operation of right kidney. Two weeks later the uninephrectomized rats were given intravenous injection of streptozotocin (STZ, 35 mg/kg). The diabetic rats were randomly divided into the following four groups: DM + bos group (bosentan 100 mg/kg/d by gavage); DM + ena group (enalapril 10 mg/kg/d by gavage); DM + bos + ena group (the same doses of both bosentan and enalapril by gavage); DM + veh group (only buffer by gavage). Besides, uninephrectomized rats without STZ injection were assigned as control group. Each group consisted of 6 rats. Twenty weeks later, they were sacrificed and left kidney of each rat was harvested respectively. The mRNA expression of angiotensinogen (Ao), angiotensin type 1 receptor (AT1R), preproendothelin-1 and endothelin A receptor (ETaR), and the protein expression of AngII, AT1R, ET-1 and ETaR in kidney tissue were semi-quantitatively detected with reverse transcription- polymerase chain reaction and immunohistochemical staining respectively.. In the diabetic group without treatment (DM + veh group), the expression of Ao (AII), AT1R and ET-AR was significantly up-regulated (1.25, 1.94 and 2.56-folds in mRNA respectively, 2.52, 3.84 and 3.30-folds in protein respectively, P < 0.01 or P < 0.05) compared with control group. In three treatment groups, i.e. DM + bos group, DM + ena group and DM + bos + ena group, the up-regulated expression of Ao (AII), AT1R and ET-AR was significantly attenuated (-38.2% to -54.8% in mRNA and -55.3% to -69.7% in protein, P < 0.05 or P < 0.01) compared with DM group. The inhibitory rates among these three treatment groups had no significant difference (P > 0.05). In this study, the expression of preproendothelin-1 mRNA and ET-1 protein was not significantly changed among all groups (P > 0.05).. Either endothelin receptor antagonist or ACE inhibitor can significantly inhibit the expression of AngII, AT1R and ETaR in kidney tissue of diabetic rats, which suggest that there are close relationship and cross action between ET-1 and AngII.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Endothelin-1; Male; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; RNA, Messenger

To study the renal protective effect of sodium ferulate (SF) and its mechanism in rats with diabetic mellitus (DM).. DM rats induced by streptozotocin were treated with SF 110 mg/kg per day for 8 weeks. The ratio of kidney weight/body weight (KW/BW), serum triglyceride (TG) and total cholesterol (TC), creatinine clearance rate (Ccr), urinary protein/24 hrs, levels of endothelin-1 (ET-1) and nitric oxide (NO) in renal cortex in rats were measured, the pathological change of kidney were observed and the expression of transforming growth factor-beta 1 (TGF-beta 1) and collagen IV (C-IV) in kidney were examined using immunohistochemical assay. The data obtained were compared with those obtained from untreated DM rats and normal rats respectively.. Compared with the normal rats, in DM rats, Ccr, urinary protein/24 hrs, ET-1, expressions of TGF-beta 1 and C-IV were significantly increased in DM model rats (all P < 0.01), and significantly abnormal pathological change in kidney was found. While in the SF treated DM rats, the above-mentioned abnormal changes were all significantly improved.. SF has effect in protecting kidney of DM rats, the mechanism might be related with its actions of reducing ET-1 production in kidney and inhibiting the expressions of TGF-beta 1 and C-IV.

Topics: Animals; Collagen Type IV; Coumaric Acids; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Kidney; Male; Protective Agents; Random Allocation; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1

Two endothelium-derived factors, endothelin (ET), a vasoconstrictor, and vascular endothelial growth factor (VEGF), an angiogenic factor are thought to be involved in the pathogenesis of diabetic vascular complications. The aim of this study was to determine the effects of an angiotensin II type I (AT-1) receptor antagonist and an ACE inhibitor on the pathogenesis of VEGF and ET-1-mediated kidney disease in STZ-induced diabetic rats. Two days after STZ administration, diabetic rats were treated for 8 weeks with enalapril maleate, an ACE inhibitor, candesartan cilexetil, an AT-1 receptor antagonist, or saline. Urinary albumin and N-acetyl beta-D glucosaminidase (NAG) excretion as well as the VEGF protein content in the kidney were all found to be elevated in diabetic rats. Administration of enalapril maleate or candesartan cilexetil decreased the level of microalbuminuria and NAG excretion in diabetic rats. Administration of enalapril maleate also suppressed the elevated renal VEGF protein content in these animals while candesartan cilexetil treatment had no effect. Serum ET-1 and VEGF levels were unchanged by these treatments. These data support a role for AT-1 receptor antagonists and ACE inhibitors in the prevention of diabetic nephropathy, and suggest that the former may work by reducing renal VEGF levels.

Topics: Albuminuria; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Enalapril; Endothelin-1; Kidney; Male; Rats; Rats, Wistar; Streptozocin; Tetrazoles; Vascular Endothelial Growth Factor A

We have investigated the protective effect of YM598, a selective endothelin type A receptor antagonist, against an endothelin-1-induced proliferation of rat mesangial cells and renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598, but not K-8794, a selective endothelin type B receptor antagonist, inhibited the endothelin-1-induced proliferation of cultured mesangial cells derived from intact Wistar rats in a concentration-dependent manner. YM598 (0.1 or 1 mg/kg), enalapril (5 mg/kg), an angiotensin- converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. YM598 blunted the development of albuminuria in a dose-dependent manner. A higher dose of YM598 reduced albuminuria comparable with enalapril. Urinary endothelin-1 excretion was greater in the diabetic rats than in the control rats, and was not substantially influenced by the agents. Enalapril, but not YM598, mildly lowered the blood pressure in the diabetic rats, indicating that blood pressure reduction is not involved in the major mechanism of the renoprotective effect of YM598 in OLETF rats. These data suggest that endothelin is involved in the progression of diabetic nephropathy in OLETF rats, and an endothelin type A antagonist is promising for the treatment of diabetic nephropathy.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Endothelin A Receptor Antagonists; Endothelin-1; Hyperplasia; Male; Mesangial Cells; Pyrimidines; Rats; Rats, Inbred OLETF; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

To investigate the possible mechanism of angiotensin II receptor blockage (Losartan) for the decreasing of proteinuria and the protection of renal function in diabetic rats.. Sixty Wistar rats were divided into 3 groups: Losartan treatment group, diabetes mellitus (DM) model group, and control group. All were treated accordingly for 4 weeks. 24 hours urine protein count, creatinin clearance rate (Ccr), mean arterial pressure (MAP), kidney weight/body weight, ET-1 in blood and urine, IV collagen and fibronectin (FN) in kidney tissue were determined at 1, 2, 4 weeks.. In DM model group, the 24 hours urine protein count and MAP, compared with control, increased significantly (P < 0.05) and reached peak at 2 weeks; the decrease of Ccr and the increase of kidney weight/body weight were observed; meanwhile, by immunohistochemistry, increased expression levels of FN, IV collagen were shown in kidney tissues, especially on basement membrane, and significant increase of ET-1 level in blood and urine was also noted. In Losartan treatment group, all of MPA, 24 hours urine protein count, kidney weight/body weight and Ccr decreased, compared with those of model group; ET-1 in blood and urine decreased too, especially the decreasing of ET-1 in urine (P < 0.01). And the expression level of FN and IV collagen was just as small as that in control group.. Losartan may play a role in inhibiting the synthesis and secretion of ET-1 in kidney and thus it will contribute to the decreasing of proteinuria and the protection of renal function.

Topics: Angiotensin Receptor Antagonists; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Kidney Function Tests; Losartan; Male; Rats; Rats, Wistar

The pathomechanisms that cause renal damage in diabetes have not been completely clarified. Treatment with angiotensin-converting enzyme inhibitors (ACE-i) is highly effective but fails to completely prevent end-stage renal disease. The effects of ET(A)-receptor blockers (ET(A)-RB) on renal damage are controversial and have rarely been investigated in type 2 diabetes. We compared the influence of the selective ET(A)-RB LU135252 and the ACE-i Trandolapril on renal structure in the SHR/N-cp rat model of type 2 diabetes. Three-month-old male SHR/N-cp rats were left untreated or received daily either Trandolapril or LU135252. The experiment was terminated after 6 months. The glomerulosclerosis index; tubulointerstitial damage index; and glomerular geometry, glomerular cell number, and capillary density were investigated. Proliferating cell nuclear antigen and desmin expression of podocytes, renal mRNA expression of endothelin (ET-1) and transforming growth factor-beta, blood pressure, and urine albumin excretion were measured. The glomerulosclerosis index was significantly higher in untreated diabetic animals than in the groups that were treated with ACE-i and ET(A)-RB. There were analogous changes in tubulointerstitial damage index. Treatment with either substance comparably lowered urinary albumin excretion in diabetic SHR/N-cp. Podocyte and endothelial cell numbers per glomerulus decreased in untreated diabetic animals; this was prevented by the ACE-i but not by the ET(A)-RB. Glomerular capillary length density was lower in SHR/N-cp, and this was normalized by ACE-i only. Increased expression of desmin and proliferating cell nuclear antigen expression of podocytes in the SHR/N-cp was abrogated by ACE-i but not by ET(A)-RB. Treatment with ACE-i or ET(A)-receptor antagonist resulted in less structural and functional alterations, but the ET(A)-RB was inferior to the ACE-i. This is particularly the case for podocyte changes pointing to angiotensin II-dependent pathomechanisms.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; Indoles; Kidney; Male; Phenylpropionates; Proliferating Cell Nuclear Antigen; Pyrimidines; Rats; RNA, Messenger; Transforming Growth Factor beta

To study the effect of the Compound of traditional Chinese drugs and Benazepril on gene expression of renal endothelin and its receptor of experimental diabetic nephropathy(DN). To discove the mechanism of the compound of traditional Chinese drugs in treating DN.. Streptozotocin DN model was built and influenced with the compound of traditional Chinese drugs and Benazepril. The changes of Upro, Glu, HbA1C and (PT-PCR) mRNA expression levels of ET-1, ETA-R of the renal cortex were tested, and thus the histopathological character of the kidney was analysed.. The compound of traditional Chinese drugs and Benazepril have significant difference from normal saline in the improvement of Upro, Glu, HbA1C. The compound of traditional Chinese drugs have significant difference from Benazepril in the improvement of Glu, HbA1C. The mRNA expression level of ET-1, ETA-R of the renal cortex of DN model was raised. After influenced by the compound of traditional Chinese drugs and Benazepril, the over-expression level de-creased (still higher than normal control ones). The compound of traditional Chinese drugs were more effective than Benazepril to inhibit the proliferation of the stalk region and the third cells.. ET takes part in the process of diabetic glo-Merulosclerosis. Both the compound of traditional Chinese drugs and Benazepril can influence the expression quantity from the level of gene transcription of ET and its receptor. The compound of traditional Chinese drugs can not only reduce urinary albumin of DN, but also improve blood glucose, glycosylated hemoglubin. And it can inhibit nonenzymatic glucosylation of protein as well as the proliferation of the stalk region and the third cells.

Topics: Animals; Benzazepines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drugs, Chinese Herbal; Endothelin-1; Gene Expression; Kidney Cortex; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger

We have investigated the effect of potassium (E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598), a selective endothelin ET(A) receptor antagonist, on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598 (0.1 or 1 mg kg(-1)), enalapril (5 mg kg(-1)), an angiotensin-converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male Otsuka Long-Evans Tokushima Fatty rats for 32 weeks. Enalapril but not YM598 mildly lowered blood pressure in the diabetic rats. YM598 blunted the development of albuminuria in a dose-dependent manner. High dose of YM598 reduced albuminuria comparable to enalapril. Urinary endothelin-1 excretion was greater in the diabetic than in the control rats, and was not substantially influenced by the agents. These data suggest that endothelin is involved in the progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats, and an endothelin ET(A) receptor antagonist may be useful for the treatment of diabetic nephropathy.

Topics: Animals; Blood Pressure; Body Weight; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Kidney Function Tests; Male; Pyrimidines; Rats; Rats, Inbred OLETF; Receptor, Endothelin A; Sulfonamides

In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self-reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late-onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin-induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8, which encodes a small basic helix-loop-helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI-3-K pathways. Small interfering RNA (siRNA)-mediated RNA interference indicates that p8 is required for endothelin-induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Diabetic Nephropathies; DNA-Binding Proteins; Endothelin-1; Gene Expression Profiling; Gene Expression Regulation; Genetic Markers; Glomerular Mesangium; Growth Substances; Humans; Hypertrophy; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Rats; RNA Interference; Signal Transduction; Transcriptional Activation

Endothelin-1 (ET-1) concentrations are increased in patients with diabetes mellitus, particularly those with diabetic retinopathy, or essential hypertension. We hypothesized that ET-1 might participate in the development and progression of diabetic microangiopathy. In this study, the effects of the angiotensin converting enzyme (ACE) inhibitor, enalapril maleate, on diabetic angiopathy were examined in streptozotocin (STZ)-induced diabetic (STZ-DM) rats by monitoring variations in renal function and ET-1 concentrations in blood and organ tissues. Significant increases in kidney weight and in concentrations of urinary albumin, N-acetyl-fl-d-glucosamidase (NAG) and serum ET-1 were observed in the STZ-DM rats as compared with the non-diabetic rats, and the concentration of ET-1 in the kidneys tended to be increased. Microscopic and electron microscopic analyses showed increased mesangial cell proliferation, matrix expansion and enlarged mesangial area in the kidney of the diabetic rats. After administration of the ACE inhibitor, increased concentrations of urinary albumin and NAG in the STZ-DM rats were reduced to the control values with a slight improvement in the electron microscopic changes. These data suggest that ET-1 may be involved in the development and progression of diabetic nephropathy and may explain, in part, why diabetes is liable to complicate hypertension. ACE inhibitor may help to restore diabetic nephropathy in the STZ-induced diabetic rats.

Topics: Acetylglucosaminidase; Albumins; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Endothelin-1; Endothelium, Vascular; Kidney; Male; Microscopy, Electron; Organ Size; Rats; Rats, Wistar

Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course.

Topics: Adolescent; Adult; Biomarkers; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Intercellular Adhesion Molecule-1; Microcirculation; Nitric Oxide; Thromboxane A2

Recently, an endothelin (ET-1) with a potent vasoconstrictive activity and stimulative activity of vascular muscular cell growth was discovered and blood ET-1 levels were higher in diabetic patients than in healthy subjects, suggesting that high ET-1 levels assist development and progression of diabetic microangiography.. We examined renal function, and serum and tissue ET-1 levels in streptozotocin (STZ)-induced diabetic rats treated with a prostaglandin (PG) I(2) derivative to investigate the effect of PGI(2) in diabetic vascular disturbance.. Renal weight, urinary albumin, urinary N-acetyl-beta,D-glucosaminidase (NAG) and serum ET-1 levels increased in STZ-induced diabetic rats, and a tendency to increase in renal tissue ET-1 levels was observed. Furthermore, electron-microscopic findings in the kidneys showed mesangial cell proliferation and mesangial matrix expansion which might be caused by diabetic nephropathy. The PGI(2) derivative reduced urinary albumin and NAG levels in STZ-induced rats. It was considered, therefore, that the PGI(2) derivative is effective in diabetic nephropathy. As the PGI(2) derivative also reduced renal tissue ET-1 levels, improvement of diabetic nephropathy partially was considered to result from the reduction of renal tissue ET-1 levels.. In STZ-induced rats, increased serum ET-1 levels and a tendency to increase in renal tissue ET-1 levels were associated with increases in urinary albumin and NAG levels, and these levels were decreased by a PGI(2) derivative. These findings suggested that increased ET-1 concentrations assist development and progression of diabetic nephropathy, especially diabetic microangiopathy, and the PGI(2) derivative may be effective for inhibition of diabetic microangiopathy mediated by reduction of ET-1 concentrations.

Topics: Albuminuria; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Epoprostenol; Fasting; Hypoglycemic Agents; Kidney; Male; Microscopy, Electron; Organ Size; Rats

Mesangial cell hypertrophy and increased extracellular matrix (ECM) contribute to mesangial expansion in early progressive diabetic nephropathy. Previous studies suggest that the growth factor endothelin-1 (ET-1) is not only up-regulated in diabetes, but may mediate the effects of hyperglycemia on mesangial cell hypertrophy and ECM synthesis. In models of diabetes mellitus, the mechanisms underlying increased ET-1 peptide and mRNA remain unknown. Therefore, our purpose is to determine whether ET-1 gene activity increases in kidneys of streptozotocin (SZT)-treated rats.. Male Sprague-Dawley rats were injected with either SZT or vehicle. Parameters including glucose, body weight, 24-hour urine volume, urinary protein, and urinary ET-1 excretion were recorded. All rats were sacrificed at 12 weeks postinjection. Prepro-ET-1 mRNA from whole kidneys was determined using both RNase protection and reverse transcription-polymerase chain reaction (RT-PCR). The abundance of ET-1 peptide in primary cultured mesangial cells was detected by indirect immunofluorescence following treatment with 5.6, 11.2, or 22.5 mmol/L D-glucose for 24 hours. Cellular ET-1 mRNA was measured using RT-PCR in control cells at time 0 and also following exposure to increasing concentrations of glucose for 24 hours. Rat mesangial cells were transfected with a luciferase reporter construct containing the rat ET-1 promoter (pET1. Luc), and relative ET-1 promoter activity was measured after a 24-hour exposure to 5.6 and 22.5 mmol/L of D- or L-glucose.. After 12 weeks of hyperglycemia, diabetic rats gained less weight (344 +/- 23.9 vs. 548.75 +/- 15.08 g), had increased urinary volume (158.6 +/- 24.32 vs. 8.38 +/- 1.56 mL/day), and had marked proteinuria (101.7 +/- 12.2 vs. 14.1 +/- 2.8 mg/day) compared with controls. Total urinary ET-1 peptide increased 26.4-fold in diabetic versus control rats (17.5083 +/- 5.405 vs. 0.6635 +/- 0.343 ng/day). ET-1 mRNA extracted from whole rat kidneys was increased 2.1-fold in diabetic versus control animals. Primary cultured rat mesangial cells demonstrated a significant increase in immunofluorescence labeling of ET-1 peptide and ET-1 mRNA in response to increasing concentrations of glucose. Furthermore, transfected mesangial cells exposed to 22.5 mmol/L D-glucose showed a 1.6-fold increase in ET-1 promoter activity relative to those treated with 5.6 mmol/L glucose.. Glucose increases ET-1 gene expression in the kidney of the SZT-treated rat model of diabetes mellitus. Furthermore, high glucose induces ET-1 expression in primary cultured rat mesangial cells and directly enhances ET-1 promoter activity. The greater relative increase in peptide compared with transcription suggests the potential participation of other mechanisms such as increased mRNA stability, protein stability, and/or enhanced translational efficiency.

Topics: Animals; Blood Glucose; Body Weight; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Endothelins; Extracellular Matrix; Gene Expression; Glomerular Mesangium; Glucose; Hyperglycemia; Male; Promoter Regions, Genetic; Protein Precursors; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic; Transfection; Urine; Vasoconstriction

Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans.. The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software.. Significant evidence for association with ESRD was detected for alleles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies).. Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.

Topics: Adult; Amino Acid Substitution; Base Sequence; Black or African American; Black People; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Exons; Genetic Markers; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Microsatellite Repeats; Minisatellite Repeats; Molecular Sequence Data; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; North Carolina; Nuclear Family

To observe the effect of Tangweikang capsule (TWKC) in treating diabetic nephropathy (DN).. The 119 patients enrolled were divided into 2 groups, 78 patients in the TWKC group treated with TWKC and 41 patients in the control group treated with Captopril. The changes of symptom score, urinary microprotein series (urinary albumin excretion rate, Tamm-horsfall protein and beta 2-microglobulin), blood glucose, kidney function, blood lipid, angiotensin I (A I) and II (A II), atrial natriuretic polypeptide (ANP), thromboxane B2(TXB2), 6-keto-prostaglandin F1 alpha, endothelin 1 (ET-1) and collagen IV in patients after treatment were observed.. The total effective rate in the TWKC group was 84.62%, which was superior to that in the control group (70.73%, P < 0.05). TWKC also showed better effects in improving clinical symptoms, lowering blood glucose, urinary microprotein series, blood lipid, A I, A II, ANP, ET-1 and collagen IV, ameliorating kidney function, and adjusting dynamic equilibrium of thromboxane-prostacyclin system, as compared with the control group (P < 0.05 or P < 0.01).. TWKC could lower the levels of blood glucose and lipid, improve the glucose and lipid metabolism, regulate the microcirculation, ameliorate the degree of kidney damage, therefore, it showed a better effect in treating diabetic nephropathy.

Topics: Adult; Aged; Albuminuria; beta 2-Microglobulin; Capsules; Collagen; Diabetic Nephropathies; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Male; Middle Aged; Phytotherapy

Nephropathy is an important complication of diabetes mellitus (DM). The plasma endothelin 1 (ET-1) levels are increased in DM, and ET-1 may cause deleterious effects on renal function. We, therefore, investigated whether changes in ET receptors occur in the DM rabbit kidney.. Nine adult New Zealand White rabbits were injected with alloxan, of which 6 became diabetic; the other 3 acted as alloxan-treated controls. Six age-matched healthy rabbits served as controls. At 6 months, following cervical dislocation, the kidneys were removed, and sections (cortex and medulla) were incubated with ET(A) and ET(B) radioligands to produce low- and high-resolution autoradiographs. Immunohistochemical localization of ET-1 immunoreactivity was also performed.. There was greater ET(A) and ET(B) receptor binding in the control (ET(A) p = 0.0003; ET(B) p < 0.0001) and DM (ET(A) p = 0.001; ET(B) p < 0.0001) rabbits in the medulla as compared with the cortex. DM kidneys showed a significant increase in ET(A), but not ET(B), binding in the cortex (p < 0.0001) and in the medulla (p < 0.0001). High-resolution autoradiographs revealed striking [(125)I]-ET-1 receptor binding predominantly to the glomeruli. Immunohistochemistry revealed dense ET-1 immunoreactivity associated with the renal tubules, but the glomeruli exhibited no staining. Alloxan-treated controls had similar results to age-matched controls.. There are regional differences in both ET(A) and ET(B) binding in control and DM kidneys. ET(A) receptor binding sites are increased in the DM kidney (cortex and medulla). ET-1 may act in a paracrine fashion on the glomeruli. These changes may contribute to the pathogenesis of diabetic nephropathy.

Topics: Alloxan; Animals; Autoradiography; Azepines; Blood Glucose; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Endothelin-1; Endothelins; Immunoenzyme Techniques; Iodine Radioisotopes; Kidney; Male; Oligopeptides; Peptide Fragments; Potassium; Rabbits; Radioligand Assay; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sodium; Up-Regulation

Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET(A) receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury. Here we investigated whether an unselective ET(A)/ET(B) receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes. PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats. Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better. Northern blot analysis of ET-1 mRNA revealed upregulation of ET-1 gene in the diabetic kidney. Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats. Both treatments remarkably attenuated exaggerated renal ET-1 gene expression. These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cohort Studies; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Follow-Up Studies; In Situ Hybridization; Kidney; Lisinopril; Male; Oligopeptides; Pilot Projects; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors

To evaluate the role of circulating and renal endothelin-1 (ET-1) in early diabetic nephropathy, plasma ET-1 levels and urinary ET-1 excretion were evaluated in lean, normotensive patients affected by non-insulin-dependent diabetes (NIDDM) either with (n = 9, NIDDM+) or without microalbuminuria (n = 18, NIDDM-); in never-treated, lean, essential hypertensive patients with (n = 12, EH+) or without microalbuminuria (n = 10, EH-); and in healthy volunteers (n = 12). Results showed higher plasma ET-1 levels in NIDDM+ (1.97 +/- 0.58 pg/mL) than in NIDDM- (1.59 +/- 0.14 pg/mL, P = .013), EH+ (1.40 +/- 0.21 pg/mL, P = .005), EH- (0.91 +/- 0.19 pg/mL, P < .0001), and controls (0.60 +/- 0.10 pg/mL, P < .0001). The circulating ET-1 concentration was also higher in EH+ than EH- and controls (P < .0001). Urinary ET-1 excretion did not differ (P = .387, NS) between NIDDM+ (48.5 +/- 20.1 pg/min) and NIDDM- (40.9 +/- 21.6 pg/min), but was significantly reduced (P < .0001) in both groups compared with controls (70.0 +/- 15.5 pg/min). Similar findings were observed in hypertensive subgroups. No correlations were found between urinary ET-1 and other variables, including plasma ET-1 levels, in all groups. In conclusion, NIDDM+ is accompanied by a significant increase in plasma ET-1 levels. A significant elevation of circulating ET-1 concentration was evident also in NIDDM-, suggesting that early abnormalities of ET-1 production might precede the microalbuminuric phase of diabetes-related renal damage.

Topics: Adult; Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged

To evaluate the secretion of vasoactive factors in vascular endothelium of patients with non-insulin-dependent diabetes mellitus (NIDDM) the authors examined 31 NIDDM patients. Of them, 18 had no signs of renal involvement, 13 patients showed apparent diabetic nephropathy (DN). In the former patients the blood contained much greater content of vasodilating factor prostacyclin than of vasoconstricting factor endothelin-1 (ET-1) and thromboxan A2 (TxA2). In diabetic nephropathy the balance of vasoactive factors shifted to predominance of vasoconstrictors ET-1 and TxA2. Such rearrangement of vasoactive factors to higher quantities of vasoconstrictors in diabetes mellitus may initiate or promote progression of diabetic nephropathy with resultant spasm of afferent glomerular vessels, reduced glomerular filtration and renal blood flow rates, arterial hypertension, increased thrombogenesis. Thus, elevated levels of ET-1 and TxA2 in diabetics and their rise with progression of diabetic nephropathy are likely to act as pathogenetic factors underlying onset and progression of nephroangiopathy.

Topics: Albuminuria; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2

To assess whether plasma and urinary endothelin-1 (ET-1) values are related to the severity of diabetic nephropathy, we measured plasma and urinary ET-1-like immunoreactivity (ET-1-LI) in 14 healthy subjects, and in 50 normoalbuminuric (group 1), 13 albuminuric (group 2), and 10 renally insufficient (group 3) patients with Type 2 diabetes. Plasma ET-1-LI values were significantly increased in group 3, and correlated positively with serum creatinine levels (r = 0.579, p < 0.01). Urinary ET-1-LI excretion in group 3 (49.3 +/- 7.3 pmol day-1) was significantly higher than that in healthy controls (27.0 +/- 1.1 pmol day-1) and in group 1 (32.2 +/- 2.2 pmol day-1), while that of group 2 (38.8 +/- 5.9 pmol day-1) was also higher than in healthy controls. A significant positive correlation between urinary ET-1-LI and serum creatinine values was also found (r = 0.297, p < 0.05). Trend analysis showed significant linear and quadratic trends in the elevation of plasma ET-1-LI and a significant linear trend in urinary ET-1-LI levels from healthy controls to groups 1, 2 and 3. Our results demonstrate that an increase in plasma and urine ET-1-LI correlates with the severity of diabetic nephropathy.

Topics: Albuminuria; Biomarkers; China; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Humans; Kidney Diseases; Middle Aged