Exercise-induced alterations in phospholipid hydrolysis, airway surfactant, and eicosanoids and their role in airway hyperresponsiveness in asthma.

The mechanisms responsible for driving endogenous airway hyperresponsiveness (AHR) in the form of exercise-induced bronchoconstriction (EIB) are not fully understood. We examined alterations in airway phospholipid hydrolysis, surfactant degradation, and lipid mediator release in relation to AHR severity and changes induced by exercise challenge. Paired induced sputum (n = 18) and bronchoalveolar lavage (BAL) fluid (n = 11) were obtained before and after exercise challenge in asthmatic subjects. Samples were analyzed for phospholipid structure, surfactant function, and levels of eicosanoids and secreted phospholipase A2 group 10 (sPLA2-X). A primary epithelial cell culture model was used to model effects of osmotic stress on sPLA2-X. Exercise challenge resulted in increased surfactant degradation, phospholipase activity, and eicosanoid production in sputum samples of all patients. Subjects with EIB had higher levels of surfactant degradation and phospholipase activity in BAL fluid. Higher basal sputum levels of cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) were associated with direct AHR, and both the postexercise and absolute change in CysLTs and PGD2 levels were associated with EIB severity. Surfactant function either was abnormal at baseline or became abnormal after exercise challenge. Baseline levels of sPLA2-X in sputum and the absolute change in amount of sPLA2-X with exercise were positively correlated with EIB severity. Osmotic stress ex vivo resulted in movement of water and release of sPLA2-X to the apical surface. In summary, exercise challenge promotes changes in phospholipid structure and eicosanoid release in asthma, providing two mechanisms that promote bronchoconstriction, particularly in individuals with EIB who have higher basal levels of phospholipid turnover.

Cyclodextrin protects podocytes in diabetic kidney disease.

Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD(+)) when compared with diabetic patients with normoalbuminuria (DKD(-)) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.

Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.

FGF23 induces left ventricular hypertrophy.

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Manejo de la dislipidemia en el paciente diabético tipo 2 / Dyslipidemia management in type 2 diabetic patient

Los niveles de colesterol de baja densidad parecen ser la anormalidad con mayor repercusión en pacientes diabéticos tipo 2 por ser más aterogénico, incluso sin aumentos significativos. En muchos pacientes sólo el control glucémico y los cambios en el estilo de vida pueden lograr controlar los niveles de colesterol, pero no siempre hasta niveles deseables. La terapia agresiva para disminuir el colesterol de baja densidad en pacientes con alto riesgo de enfermedad coronaria disminuye los eventos coronarios agudos por lo que la reducción del colesterol de baja densidad, con aumento del colesterol de alta densidad, son el objetivo primario. Se ha propuesto como meta secundaria el control de factores asociados al síndrome metabólico (con el colesterol no HDL como meta), y como tercer objetivo la normalización de las lipoproteínas de alta densidad o de la relación colesterol/lipoproteínas de alta densidad. Las estatinas son los agentes de elección en el manejo de las dislipidemias en pacientes con diabetes mellitus tipo 2 sin hipertrigliceridemia significativa; disminuyen los niveles de colesterol de baja densidad y pueden administrarse como monoterapia o terapia combinada de acuerdo a los requerimientos del paciente. Los fibratos han probado su efectividad cuando habiéndose alcanzado las metas en los niveles de lipoproteínas de baja densidad, las otras no se han obtenido e incluso en pacientes con niveles de lipoproteínas de alta densidad aislado. El abordaje de la dislipidemia, se basa en el inicio temprano, agresivo y persistente del manejo farmacológico, para lograr reducir consecuencias en estos pacientes considerados equivalentes coronarios.

High levels of low density lipoprotein (LDL) cholesterol seem to be the abnormality with a greater repercussion among type 2 diabetic patients, due to the fact that they are more atherogenitic, by themselves, even with minor increases. In many patients only with the control of their glucemia and changing their life style, can they frequently manage to control the cholesterol levels to some extent but never reaching normal values? Many studies show that aggressive therapy to diminish the low density lipoprotein cholesterol in patients with high risk of coronary disease diminishes, significantly, the acute coronary events. This is one of the reasons why the reduction of LDL and the increase of the high density lipoprotein (HDL) cholesterol, is the main goal for handling of Dyslipidemia in these patients. The control of connected factors of the Metabolic Syndrome most be the second goal (with non-HDL cholesterol as objective); and as a third objective, has to be, the normalization of high density lipoproteins (HDL), as well as the relation cholesterol/high density lipoproteins. The statins are the election agents in the handling of Dyslipidemia in patients with significant type 2 diabetes mellitus without hipertrygliceridemia. They lower the cholesterol levels and the low density lipoprotein. They also can be given as single therapy. The fibrates have proven their effectiveness when LDL levels have been reached but no the others. The main goal to treat Dyslipidemia is based upon an early, aggressive and persistent pharmacologic intervention in order to reduce the bad prognosis in these patients, mainly in terms of potential coronary events.