Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment.

Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages. Mstn co-localized with α-smooth muscle actin (α-SMA) staining and with some CD45+ cells, indicating Mstn expression in VSMCs and bloodstream-derived leukocytes. In vitro, Mstn was tested in VSMCs and monocytes. In A7r5 VSMCs, Mstn downregulated proliferation and Smoothelin mRNA, induced cytoskeletal rearrangement, increased migratory rate and MCP-1/CCR2 expression. In monocytes (THP-1 cells and human monocytes), Mstn acted as a chemoattractant and increased the MCP-1-dependent chemotaxis, F-actin, α-SMA, MCP-1 and CCR2 expression; in turn, MCP-1 increased Mstn mRNA. Mstn induced JNK phosphorylation both in VSMCs and monocytes. Our results indicate that Mstn is overexpressed in abdominal aortic wall deterioration, affects VSMCs and monocyte biology and sustains a chronic inflammatory milieu. These findings propose to consider Mstn as a new playmaker in atherosclerosis progression.

Metabolic syndrome is associated with left ventricular dilatation in primary hypertension.

Metabolic syndrome (MS) has been shown to predict cardiovascular events in hypertension. Recently, a new four-group left ventricular (LV) hypertrophy classification based on both LV dilatation and concentricity was proposed. This classification has been shown to provide a more accurate prediction of cardiovascular events, suggesting that the presence of LV dilatation may add prognostic information. We investigated the relationship between MS and the new classification of LV geometry in patients with primary hypertension. A total of 372 untreated hypertensive patients were studied. Four different patterns of LV hypertrophy (eccentric nondilated, eccentric dilated, concentric nondilated and concentric dilated hypertrophy) were identified by echocardiography. A modified National Cholesterol Education Program definition for MS was used, with body mass index replacing waist circumference. The overall prevalence of MS and LV hypertrophy (LVH) was 29% and 61%, respectively. Patients with MS showed a higher prevalence of LVH (P=0.0281) and dilated LV geometries, namely eccentric dilated and concentric dilated hypertrophy (P=0.0075). Moreover, patients with MS showed higher LV end-diastolic volume (P=0.0005) and prevalence of increased LV end-diastolic volume (P=0.0068). The prevalence of LV chamber dilatation increased progressively with the number of components of MS (P=0.0191). Logistic regression analysis showed that the presence of MS entails a three times higher risk of having LV chamber dilatation even after adjusting for several potential confounding factors. MS is associated with LV dilatation in hypertension. These findings may, in part, explain the unfavourable prognosis observed in patients with MS.

Effects of peritoneal dialysis on protein metabolism.

Protein-energy wasting is relatively common in renal patients treated with haemodialysis or peritoneal dialysis (PD) and is associated with worse outcome. In this article, we review the current state of our knowledge regarding the effects of PD on protein metabolism and the possible interactions between PD-induced changes in protein turnover and the uraemia-induced alterations in protein metabolism. Available evidence shows that PD induces a new state in muscle protein dynamics, which is characterized by decreased turnover rates and a reduced efficiency of protein turnover, a condition which may be harmful in stress conditions, when nutrient intake is diminished or during superimposed catabolic illnesses. There is a need to develop more effective treatments to enhance the nutritional status of PD patients. New approaches include the use of amino acid/keto acids-containing supplements combined with physical exercise, incremental doses of intraperitoneal amino acids, vitamin D and myostatin antagonism for malnourished patients refractory to standard nutritional therapy.

Evaluation of metabolic acidosis in patients with a kidney graft: comparison of the bicarbonate-based and strong ion-based methods.

BACKGROUND: According to the traditional bicarbonate-based approach, metabolic acidosis is highly prevalent in kidney transplant recipients. However, the bicarbonate-based approach has been questioned by intensivists using strong ion difference-based methods. METHODS: We compared the results obtained by the strong ion-based with the traditional approach based on bicarbonate among a cohort of 83 kidney transplant recipients. RESULTS: Fifty-five percent of the patients were acidotic based on venous bicarbonate (<23 mmol/L) and 49% by the use of the effective strong ion difference (SID(effective)) (<37 mmol/L). Bicarbonate and SID(effective) were linearly correlated (r=0.94; P<.0001), with a slope close to 1. A greater percentage of patients presented with an increase in unexplained anions by the strong ion gap (SIG) than by the anion gap corrected (AG(corrected)) method (42 vs 32%, respectively). AG(corrected) and SIG were directly related (r=0.919; P<.0001), but the best fit of the relationship was polynomial with a progressively greater effect on SIG with increased AG(corrected), suggesting that as anions progressively accumulate, their detection by SIG increases. By multiple regression analysis, plasma chloride, potassium, uric acid, and phosphate predicted blood bicarbonate. Analogously, chloride, potassium and uric acid predicted SID(effective). Age was a predictor of changes in AG(corrected), whereas age and plasma urea predicted SIG. CONCLUSIONS: The use of the SID yielded results that were similar to the traditional bicarbonate-based approach. Conversely, SIG appeared to be more sensitive than AG for detection of anion accumulation among patients with a kidney graft.

Apoptosis in the kidneys of patients with type II diabetic nephropathy.

The occurrence and extent of apoptosis in the kidneys of patients with diabetic nephropathy is largely unknown. We evaluated apoptosis in renal biopsies obtained from patients with early or advanced type II diabetic nephropathy. Apoptosis was about 6- and 3-fold higher, respectively, in glomeruli and tubules in kidneys of patients with early nephropathy than in the normal kidney and this was not further increased in advanced diabetic nephropathy. Glomerular apoptosis was related directly to hemoglobin A1(c) and systolic blood pressure, whereas tubular cell apoptosis correlated to diabetes duration and low-density lipoprotein-cholesterol. Fas, Fas ligand, and p38 mitogen-activated protein kinase expressions were enhanced in glomeruli and tubules; however, this did not correlate with apoptosis. In patients with proteinuria, apoptosis was associated with the subsequent loss of kidney function. When these parameters were subjected to multivariate analysis, only glomerular apoptosis retained a significant independent predictive value. Our findings suggest that apoptosis might be a clinically relevant mechanism of glomerular and tubular cell loss in proteinuric type II diabetic patients.

Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state.

To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia.

Gender and the progression of chronic renal diseases: does apoptosis make the difference?

Several studies in patients with chronic kidney diseases have shown that men have a more rapid disease progression than women. Also, with ageing, men exhibit greater decrements in renal function and increased glomerular sclerosis than women. Data from meta-analysis studies indicate that women with several non-diabetic renal diseases such as membranous nephropathy, IgA nephropathy and polycystic kidney disease present a slower progression, but in diabetic renal disease this is not yet established. Thus, men appear to be at greater risk for renal injury than are women, but the underlying mechanisms are unknown. Sex hormones may mediate the effects of gender on chronic renal disease, through the interaction with the renin-angiotensin system, the modulation of nitric oxide synthesis and the downregulation of collagen degradation. New observations indicate that androgens may contribute to continuous loss of kidney cells though the stimulation of apoptotic pathways. Apoptosis is an unique type of programmed cell death which is activated in several chronic kidney diseases. Studies in vitro indicate that androgens prime a Fas/FasL dependent apoptotic pathway in kidney tubule cells. This apoptotic cell death pathway is receptor-linked and interacts with the mitochondrial pathway, which may be activated by other mechanisms, such as toxins and ischemia. Therefore, the mechanisms to cell death which are primed by androgens may interact with others occurring in several conditions leading to the loss of renal cells. These findings are consistent with a role for androgens to promote chronic renal injury in men.

[Acute effects of peritoneal dialysis on muscle protein turnover]. / Effetti acuti della dialisi peritoneale sul metabolismo proteico.

BACKGROUND: Despite continuing glucose absorption and stimulation of insulin secretion, wasting is common in patients with chronic renal failure (CRF) treated with peritoneal dialysis. METHODS: To evaluate if peritoneal dialysis per se has any effect(s) on muscle protein turnover we employed the forearm perfusion method associated with the kinetics of 3H-phenylalanine in seventeen patients with CRF in the basal state and: a) during the systemic hyperinsulinemia associated with peritoneal dialysis (6 patients) (200-240 min); b) during locally-induced hyperinsulinemia, without systemic effects on aminoacid (AA) availability (6 patients) (80-120 min); c) in time-controls (5 patients) (80-240 min). RESULTS: Peritoneal dialysis and local infusion of insulin in the brachial artery (0.01 mU/min/kg) induced a similar degree of systemic or local, moderate hyperinsulinemia (19+/-4 e 21+/-3 microU/ml, respectively). During both protocols an insulin-related inhibition of muscle protein degradation occurred; however peritoneal dialysis caused a 20% decrease in forearm phenylalanine rate of disposal (an index of muscle protein synthesis), which correlated with the decline of arterial BCAA and potassium, which were removed via the peritoneal fluid. Furthermore, a persistent negative net phenylalanine and AA balance across the forearm was observed during peritoneal dialysis, while the negative basal net phenylalanine and AA balance was reversed to a positive or neutral one during local hyperinsulinemia. CONCLUSIONS: We conclude that in CRF patients even a modest elevation in local insulin levels is followed by an anabolic muscle response, while the same effect is not observed during the systemic hyperinsulinemia associated with substrate removal which occurs during peritoneal dialysis. In this setting the antiproteolytic effect of hyperinsulinemia is offset by a decrease in muscle protein synthesis which is accounted for by a decrease in AA availability. Our data indicate that protein metabolism during peritoneal dialysis is characterized not only by decreased, but also less efficient, turnover rates.

Apoptosis induced by serum withdrawal in human mesangial cells. Role of IGFBP-3.

Apoptosis has been reported to occur both during the course of kidney development and the progression of kidney injury to scarring. Insulin-like growth factor binding protein-3 (IGFBP-3), a component of the IGF system, has been shown to induce apoptosis in cancer cell lines. However, if IGFBP-3 has similar effects in human mesangial cells (HMC) remains unknown. The purpose of this study was to examine the expression of IGFBP-3 and its possible effect on the induction of apoptosis in HMC during serum deprivation. We have observed that IGFBP-3 accumulates progressively in HMC in which serum has been withdrawn. In these cells, an increase of IGFBP-3 is observed before the production of apoptosis suggesting a link between these phenomena. Furthermore, the addition of IGFBP-3 in physiological amounts (from 100 to 400 ng/ml) to culture medium devoid of growth factors accelerates and increases the apoptotic process with a dose-dependent effect. These findings suggest that IGFBP-3 is a mediator of cell death in human mesangial cells when the availability of growth factors is curtailed. These data also suggest that IGFBP-3 could contribute to apoptotic processes observed in human disease.