Role of Nrf2 dysfunction in uremia-associated intestinal inflammation and epithelial barrier disruption.

Background: Gut inflammation is prevalent in chronic kidney disease (CKD) and likely contributes to systemic inflammation via disruption of the epithelial tight junction with subsequent endotoxin and bacterial translocation.

Aims: To study the expression profile of inflammatory and tight junction proteins in the colon from CKD rats compared to healthy controls, and demonstrate the role of Nrf2 (transcription factor nuclear factor erythroid 2-related factor 2) using a potent Nrf2 activator.

Methods: CKD was induced via 5/6 nephrectomy in Sprague-Dawley rats, and dh404 (2 mg/kg/day) was used to study the effects of systemic Nrf2 activation.

Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction.

Background: Integrity of the tight junction (TJ) which seals the gap between the epithelial cells of the gastrointestinal tract is critical in preventing the entry of the microbial toxins, antigens, and other harmful products in the subepithelial tissues and the internal milieu. By enabling the absorption of these products, impairment of the intestinal epithelial barrier leads to local and systemic inflammation. We have recently found depletion of the key protein constituents of colonic epithelial TJ in animals with chronic kidney disease (CKD).

Chronic kidney disease alters intestinal microbial flora.

The population of microbes (microbiome) in the intestine is a symbiotic ecosystem conferring trophic and protective functions. Since the biochemical environment shapes the structure and function of the microbiome, we tested whether uremia and/or dietary and pharmacologic interventions in chronic kidney disease alters the microbiome. To identify different microbial populations, microbial DNA was isolated from the stools of 24 patients with end-stage renal disease (ESRD) and 12 healthy persons, and analyzed by phylogenetic microarray.

Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.

Background: Inflammation is a constant feature and a major mediator of the progression of chronic kidney disease (CKD) and its numerous complications. There is increasing evidence pointing to the impairment of intestinal barrier function and its contribution to the prevailing inflammation in advanced CKD. Under normal condition, the intestinal epithelium and its apical tight junction prevent entry of the luminal microorganisms, harmful microbial by-products and other noxious contents in the host's internal milieu.

Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression.

Background: Chronic renal failure (CRF) is associated with hypertriglyceridemia and impaired clearance of very low density lipoprotein (VLDL) and chylomicrons which are largely due to lipoprotein lipase (LPL) deficiency/dysfunction. After its release from myocytes and adipocytes, LPL binds to the endothelium in the adjacent capillaries where it catalyzes hydrolysis of triglycerides in VLDL and chylomicrons. The novel endothelium-derived molecule, glycosylphosphatidylinositol-anchored binding protein 1 (GPIHBP1), plays a critical role in LPL metabolism and function by anchoring LPL to the endothelium and binding chylomicrons.

Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD).

Background: Chronic kidney disease (CKD) results in accelerated atherosclerosis that is primarily caused by inflammation, oxidative stress and impaired triglyceride and HDL metabolisms. Several plasma proteins including phospholipid transfer protein (PTLP), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) affect HDL metabolism. PLTP transfers phospholipids and free cholesterol from triglyceride-rich lipoproteins to HDL, phospholipids between HDL particles and facilitates cholesterol efflux from cells.

Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence.

Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence.

Low albumin levels increase endothelial NO production and decrease vascular NO sensitivity.

Background: Hypoalbuminaemia is associated with increased risk of cardiovascular disease. It is unclear whether endothelial dysfunction is a direct result of low albumin or whether it is caused by factors like chronic inflammation or dyslipidaemia. In this study, the effect of low albumin concentrations on endothelial nitric oxide synthase (eNOS)-dependent NO production was determined in vitro and ex vivo.

Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells.

Background: Chronic lead exposure causes hypertension and cardiovascular disease, which are associated with, and, in part, due to oxidative stress. While occurrence of oxidative stress in lead-exposed animals and cultured endothelial cells has been well-established, direct and specific evidence on the type of the reactive oxygen species (ROS) produced by lead-exposed vascular cells is lacking and was investigated.

Methods: Human coronary endothelial (EC) and vascular smooth muscle cells (VSMC) were incubated in appropriate culture media in the presence of either 1 ppm or 10 ppm lead acetate or sodium acetate (control) for 1 to 30 minutes or 60 hours.

Blood pressure response to hypoxia: role of nitric oxide synthase.

Background: Chronic exposure to hypobaric hypoxia has been shown to increase arterial pressure in genetically normal rats. The associated increase in blood pressure is unrelated to the hypoxia-induced erythrocytosis and persists indefinitely after restoration of normoxia. It is accompanied by a marked reduction in urinary excretion of nitric oxide metabolites (NOx) and is ameliorated by L-arginine supplementation.

Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria.

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system.

Reversal of biochemical and behavioral parameters of brain aging by melatonin and acetyl L-carnitine.

The potential utility of dietary supplementation in order to prevent some of the oxidative and inflammatory changes occurring in the brain with age, has been studied. The cerebral cortex of 27-month-old male B6C3F1 mice had elevated levels of nitric oxide synthase 1 (EC 1.14.

Effects of simulated microgravity on arterial nitric oxide synthase and nitrate and nitrite content.

The aim of the present work was to investigate the alterations in nitric oxide synthase (NOS) expression and nitrate and nitrite (NOx) content of different arteries from simulated microgravity rats. Male Wistar rats were randomly assigned to either a control group or simulated microgravity group. For simulating microgravity, animals were subjected to hindlimb unweighting (HU) for 20 days.

Antioxidant therapy potentiates antihypertensive action of insulin in diabetic rats.

Background: Poorly controlled longstanding diabetes frequently results in sustained hypertension (HTN) which plays a major role in the pathogenesis of diabetic nephropathy. In addition, hyperglycemia, per se, causes a reversible rise in blood pressure (BP) and increases production of reactive oxygen species (ROS). Increased ROS activity may raise BP by promoting inactivation of nitric oxide (NO) and/or nonenzymatic generation of vasoconstrictive prostaglandins from peroxidation of arachidonic acid.

Correction of long-term diet-induced hypertension and nitrotyrosine accumulation by diet modification.

Several recent studies have demonstrated that various forms of hypertension are associated with enhanced reactive oxygen species (ROS) activity. We have recently shown that long-term consumption of a diet similar to that ingested in westernized societies, containing high saturated fat and refined carbohydrate, induces oxidative stress and hypertension in normal rats. We hypothesized that diet modification may reverse diet-induced hypertension via (among other mechanisms) decreased ROS activity and improved nitric oxide (NO) availability.

Proteinuria is preceded by decreased nitric oxide synthesis and prevented by a NO donor in cholesterol-fed rats.

Background: Hypercholesterolemia decreases nitric oxide (NO) availability in the circulation and induces podocyte activation and renal injury in rats. It is unknown whether hypercholesterolemia decreases renal NO availability. To dissociate the injury-independent effect of hypercholesterolemia on renal NO availability from secondary effects of proteinuria, increasing concentrations of cholesterol were administered.

Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency.

Chronic renal failure (CRF) is associated with oxidative stress which promotes production of reactive carbonyl compounds and lipoperoxides leading to the accumulation of advanced glycation and lipoxidation end products. Reactive oxygen species (ROS) avidly reacts with nitric oxide (NO) producing cytotoxic reactive nitrogen species capable of nitrating proteins and damaging other molecules. This study tested the hypothesis that CRF results in enhanced ROS-mediated NO inactivation and protein nitration which can be ameliorated with antioxidant therapy.