Mechanisms and consequences of hypertriglyceridemia and cellular lipid accumulation in chronic kidney disease and metabolic syndrome

Hypertriglyceridemia and intracellular lipid overload are commonly present in both the chronic kidney disease (CKD) and metabolic syndrome. Hypertriglyceridemia in the metabolic syndrome arises mostly from increased lipoprotein synthesis, while that in the CKD is mainly caused by decreased catabolism. In metabolic syndrome, enhanced plasma levels of free fatty acids and triglyceride (TG) may lead to intracellular fatty acid accumulation in the kidney. However, the mechanisms by which intracellular lipid accumulation occurs in the dieased glomeruli have not been established. I provide evidence that binding/uptake of TG-rich very low-density lipoprotein by glomerular cells is increased in CKD, leading to increased endocytic accumulation of TG. I also provide evidence that cellular damage by fatty acid accumulation in the kidney is particularly severe in podocytes, leading to apoptosis and resulting in glomerulosclerosis. Collectively, these data bring new mechanistic insights into cellular lipid overload and lipotoxicity in CKD.     

Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome

The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease (CKD) in Japanese individuals with metabolic syndrome. The study population comprised 2150 Japanese individuals with metabolic syndrome, including 411 subjects with CKD [estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m²] and 1739 controls (eGFR ≥ 60 mL/min/1.73m²). The genotypes for 100 polymorphisms of 80 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that nine polymorphisms of APOE, ABCA1, PTGS1, TNF, CPB2, AGTR1, OR13G1, and GNB3 were associated (P < 0.05) with the prevalence of CKD. Among these polymorphisms, the ? 219G → T polymorphism of APOE (rs405509) was most significantly associated with CKD in Japanese individuals with metabolic syndrome.     

Restless legs syndrome and arterial stiffness in pre-dialysis chronic kidney disease

Sleep and Biological Rhythms - Despite plenty of restless legs syndrome (RLS) studies conducted with hemodialysis patients, it has been scarcely studied in patients with predialysis chronic kidney...     

Nonalcoholic fatty liver disease and the metabolic syndrome

PURPOSE OF REVIEW: Clinical, epidemiological and biochemical data strongly support the concept that nonalcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome. Insulin resistance is the common factor connecting obesity, diabetes, hypertension and dyslipidemia with fatty liver and the progression of hepatic disease to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. RECENT FINDINGS: The association of nonalcoholic fatty liver disease with the features of the metabolic syndrome has been confirmed in several epidemiological studies. The diagnostic and clinical significance of raised liver enzymes has been questioned; advanced hepatic disease may also be present in individuals with ultrasonographically detected steatosis and normal aminotransferase levels. The role of adipokines (leptin, adiponectin) and cytokines (tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta) in disease progression is probably pivotal, mediated by oxidative stress. The importance of iron accumulation in this process has not been confirmed. Treatments aimed at weight loss remain a primary option; among pharmacological interventions, insulin sensitizers (glitazones and metformin) have confirmed beneficial effects on both biochemical and histological data, but new treatments are on the horizon. SUMMARY: Nonalcoholic fatty liver disease prevalence in Western countries is high and there is a trend towards a further increase, with millions of people at risk of advanced liver disease. The epidemiological evidence, the lifestyle origin of the disease and the cost of pharmacotherapy make prevention a primary goal, and will contribute to making behavior therapy the background treatment. We need specific programs and carefully controlled, randomized studies to tackle simultaneously all the components of the metabolic syndrome.     

The influence of the inactivating agent on the antigen content of inactivated Newcastle disease vaccines assessed by the in vitro potency test

An in vitro potency test has recently been included in the European Pharmacopoeia (EP) monograph (01/2007:0870) to assess the potency of inactivated Newcastle disease (ND) vaccines. This enzyme linked immunosorbent assay (ELISA) is an attractive alternative for the existing in vivo potency tests especially with regard to the objective of the European Authorities to Replace, Reduce and Refine the use of laboratory animals for production and quality control of immunobiologicals.In the present study the influence of the inactivant on the antigen content established by ELISA was evaluated. Therefore, oil based vaccines containing similar concentrations of β-propiolactone (BPL) or formaldehyde inactivated Newcastle disease virus (NDV) were examined by ELISA and in the in vivo potency tests outlined in the EP.The results obtained demonstrate that the use of formaldehyde as inactivant lowered the in vitro potency compared to BPL as inactivant. In contrast, the in vivo potency was not affected. Therefore, the ELISA should not be used to compare the potency of commercial ND vaccines containing formaldehyde inactivated NDV with those containing BPL inactivated NDV. However, the ELISA is considered an attractive alternative for the existing in vivo potency tests since it can be used by vaccine manufacturers for the release of inactivated ND vaccines.     

The complex role of adiponectin in chronic kidney disease

Although adiponectin, an adipocytokine released from adipose tissue, is thought to have anti-atherogenic, anti-inflammatory, and insulin-sensitizing effects, it appears that high, rather than low, circulating levels of adiponectin predict increased mortality in chronic kidney disease (CKD) patients in whom the circulating levels may rise to about three times higher than the levels in healthy subjects. As it could be hypothesized that in the uremic milieu high adiponectin levels reflect protein-energy wasting, lower residual renal function and/or volume overload, this may explain, at least in part, the observed paradoxical link between hyperadiponectinemia and poor outcome in CKD. To determine the biological consequences of high circulating adiponectin levels on carbohydrate and insulin metabolism as well as relations with cardiovascular function and mortality in the uremic milieu, further studies need to take into account both high-, and low-molecular weight adiponectin moieties as well as the role of adiponectin receptors. This brief review summarizes some of the recent advances in our understanding of the complex and context-sensitive role of this elusive and intriguing adipokine in the uremic milieu.     

The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease

Aging induces morphological changes of the kidney and reduces renal function. We analyzed the low molecular weight urinary proteome of 324 healthy individuals from 2–73 years of age to gain insight on human renal aging. We observed age‐related modification of secretion of 325 out of over 5000 urinary peptides. The majority of these changes were associated with renal development before and during puberty, while 49 peptides were related to aging in adults. We therefore focussed the remainder of the study on these 49 peptides. The majority of these 49 peptides were also markers of chronic kidney disease, suggesting high similarity between aging and chronic kidney disease. Blinded evaluation of samples from healthy volunteers and diabetic nephropathy patients confirmed both the correlation of biomarkers with aging and with renal disease. Identification of a number of these aging‐related peptides led us to hypothesize that reduced proteolytic activity is involved in human renal aging. Finally, among the 324 supposedly healthy individuals, some had urinary aging‐related peptide excretion patterns typical of an individual significantly older than their actual age. In conclusion, these aging‐related biomarkers may allow noninvasive detection of renal lesions in healthy persons and show high resemblance between human aging and chronic kidney disease. This similarity has to be taken into account when searching for biomarkers of renal disease.     

Relationship between hyperuricemia and chronic kidney disease

Because approximately 70% of uric acid is excreted from the kidney, hyperuricemia occurs when renal function deteriorates. Until now, it has not been clear if the hyperuricemia seen in such renal diseases plays a role in the progression of renal disease. However, recent clinical studies show that the serum uric acid value is closely associated with hypertension in hyperuricemic patients (cross-sectional study), and also with the onset of hypertension (longitudinal study). Furthermore, one interesting report shows that treatment of hyperuricemia with allopurinol lowers blood pressure in juvenile essential hypertension patients with hyperuricemia. In addition, it is well known that hyperuricemia is closely associated with chronic kidney disease (CKD), is a risk factor for renal insufficiency in general populations, and is a poor prognostic factor of renal function in patients who also have IgA nephropathy. On the other hand, in intervention studies on hyperuricemia, the treatment of hyperuricemia with allopurinol in CKD has resulted in a fall in blood pressure and inhibition of the progression of renal damage. Conversely, the cessation of allopurinol treatment in CKD was followed by a rise in blood pressure and the development of renal damage. Furthermore, the rise of blood pressure and development of renal damage following cessation of allopurinol treatment are only seen in patients not receiving angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). This suggests that the renin angiotensin (RA) system plays an important role in the development of hypertension and renal damage from hyperuricemia.     

The role of adiponectin in pathogenesis of metabolic syndrome and cardiovascular disease

The aim of this review is to present the up-to-date data about adiponectin and it's role in pathogenesis of cardiovascular disease. Adiponectin is a hormone derived from adipose tissue which regulates energy metabolism, and plays an important role in the pathogenesis of insulin resistance. Serum levels of adiponectin are reduced in obesity, hypertension, metabolic syndrome and type 2 diabetes. Moreover, plasma adiponectin concentration is inversely associated with LDL-cholesterol, TG and is positively related to HDL-cholesterol. Recent studies have indicated that adiponectin has antiinflammatory and antiatherogenic properties. Review of the data confirmed the hypothesis that adiponectin plays an important role in pathogenesis of cardiovascular disease.     

Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease

PURPOSE OF REVIEW: Adiponectin is secreted exclusively by adipocytes, aggregates in multimeric forms, and circulates at high concentrations in blood. This review summarizes recent studies highlighting cellular effects of adiponectin and its role in human lipid metabolism and atherosclerosis. RECENT FINDINGS: Adiponectin is an important autocrine/paracrine factor in adipose tissue that modulates differentiation of preadipocytes and favors formation of mature adipocytes. It also functions as an endocrine factor, influencing whole-body metabolism via effects on target organs. Adiponectin multimers exert differential biologic effects, with the high-molecular-weight multimer associated with favorable metabolic effects (i.e. greater insulin sensitivity, reduced visceral adipose mass, reduced plasma triglycerides, and increased HDL-cholesterol). Adiponectin influences plasma lipoprotein levels by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and HDL. It thus influences atherosclerosis by affecting the balance of atherogenic and antiatherogenic lipoproteins in plasma, and by modulating cellular processes involved in foam cell formation. SUMMARY: Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions.     

Independent influence of insulin, catecholamines, and thyroid hormones on metabolic syndrome

The objective of this study was to examine whether metabolic syndrome, defined according to adult treatment panel III criteria, is associated with insulin, catecholamines, and thyroid hormones, independently of age and gender. A cohort of 651 euthyroid overweight and obese patients, 440 women and 211 men, aged 18-68 years, were examined. Central fat accumulation (indirectly measured by waist circumference), fasting thyroid-stimulating hormone (TSH), FT(3), FT(4), insulin, glucose, and lipid (cholesterol, HDL-cholesterol, and triglyceride) serum concentrations, 24-h urinary catecholamines, and the level of insulin resistance (estimated by homeostasis model assessment for insulin resistance (HOMA(IR))) were measured. Patients with metabolic syndrome showed higher insulin (P < 0.001) and FT(3) (P < 0.001) serum levels and higher 24-h urinary noradrenaline (P < 0.001) than subjects without this syndrome. The number of metabolic syndrome parameters was directly associated with insulin (P < 0.001) and FT(3) (P < 0.05) serum levels, and with 24-h urinary noradrenaline (P < 0.001) in the whole population. When a multiple regression analysis was performed with the metabolic syndrome as the dependent variable, and age, gender, and insulin, and TSH, FT(3), FT(4) serum levels, and 24-h urinary noradrenaline and adrenaline as independent variables, the metabolic syndrome maintained an independent positive association with age (P < 0.001), male sex (P < 0.001), insulin (P < 0.001), and 24-h urinary noradrenaline (P < 0.001). In conclusion, this study suggests that insulin and noradrenaline cooperate independently to the development of the metabolic syndrome.     

The influence of aerated hydration seed treatment on seed longevity as assessed by the viability equations

Aerated hydration (AH) treatments of cauliflower seeds for 12 h (12AH) and 28 h (28AH) at 20 degrees C resulted in improved or reduced storage potential of low or high vigour seeds, respectively. Seeds were stored at their initial seed moisture content (mean 5.5% mc) or at 12% mc at 10 degrees C for 12 months and at 20 degrees C for 4 months. The improved longevity of low vigour seeds was associated with increased K(i) (initial seed viability) and a reduced rate of deterioration (1/sigma) whereas the K(i) of high vigour seeds fell after 28AH and the rate of deterioration increased such that the time to lose one probit of viability decreased from 28.7 to 5.3 months at 10 degrees C and from 10.4 to 1.2 months at 20 degrees C. The improved K(i) of low vigour seeds could be explained by the reduction in the extent of deterioration after AH, as indicated by the increase in germination after cotrolled deterioration (CD), and the possible activation of metabolic repair during treatment. In contrast the reduced germination after CD of AH-treated high vigour seeds was indicative of deterioration as a result of treatment. Both high and low vigour seeds contained constitutive levels of ss-tubulin which increased during AH treatment, the increase being greater in high vigour seeds. High vigour seeds also showed an increase in the proportion of nuclear DNA present as 4C DNA, from 3% (untreated seeds) to 26% (28AH), indicative of germination advancement from the G(1) to G(2) phase of the cell cycle during treatment. This higher proportion of 4C DNA is correlated with the increased sensitivity of seeds to drying and/or storage after AH, leading to their reduced K(i) and storage potential. In contrast, there was little change in %4C in low vigour seeds. Priming in polyethylene glycol (PEG, -1.0 MPa) for 5 d or 13 d also improved the longevity of low vigour seeds stored at their initial and 12% mc at 10 degrees C for 8 months, as reflected in their laboratory and CD germination. In this case, however, the improved longevity of the low vigour seeds following 13 d priming was associated with an increase in 4C DNA from 4% (dry control) to 56% after treatment. The germination of both untreated and primed high vigour seeds remained high throughout the storage period. Increases in the rate of germination (decreased mean germination time) observed after all AH and PEG treatments were not consistently associated with an increase in the proportion of nuclei containing 4C DNA.     

The metabolic syndrome and adipocytokines

Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases.