No abstract

Atrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-tocreatinine ratios by 26.0 6 6.5% (P < 0.01) in apoE knockout (KO) mice with streptozotocin-induced diabetes consuming an atherogenic diet, without changes in gross glomerular morphology, systemic blood pressure, and blood glucose concentration. Endothelial cationic ferritin surface coverage, investigated using large-scale digital transmission electron microscopy, revealed that atrasentan treatment increases glycocalyx coverage in diabetic apoE KO mice from 40.7 6 3.2% to 81.0 6 12.5% (P < 0.05). This restoration is accompanied by increased renal nitric oxide concentrations, reduced expression of glomerular heparanase, and a marked shift in the balance of M1 and M2 glomerular macrophages. In vitro experiments with endothelial cells exposed to laminar flow and cocultured with pericytes confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point toward a role for the restoration of endothelial function and tissue homeostasis through the antialbuminuric effects of atrasentan, and they provide a mechanistic explanation for the clinical observations of reduced albuminuria with atrasentan in diabetic nephropathy.End-stage renal disease is inevitable in a majority of patients with diabetic nephropathy (1), despite optimal blood pressure treatment using drugs that interfere with the reninangiotensin system. Therefore there is a great need for additional strategies to slow the progression of chronic kidney disease in patients with diabetic nephropathy. One such strategy involves interaction with the endothelin (ET) system. Numerous studies involving experimental animal models have implicated ET in the pathogenesis of diabetic nephropathy (2). Moreover, clinical studies show promise for ET receptor antagonists in the treatment of diabetic nephropathy (3-6). This is particularly true for selective ET A receptor blockers; ET A receptor signaling seems to be involved in key renal pathophysiological processes such as the inflammatory response of renal epithelium to albumin (7), whereas stimulation of the associated concomitant ET B receptor can restore endothelial dysfunction by inducing endothelial nitric oxide (NO) production (8-10). Because actual loss of renal function is a late indicator of disease, albuminuria has been put forward as a sensitive surrogate marker for ongoing renal injury in diabetic nephropathy. In this respect ET A receptor blockers seem to have a striking

We show by cryogenic transmission electron microscopy that PbSe and CdSe nanocrystals of various shapes in a liquid colloidal dispersion self-assemble into equilibrium structures that have a pronounced dipolar character, to an extent that depends on particle concentration and size. Analyzing the cluster-size distributions with a one-dimensional (1D) aggregation model yields a dipolar pair attraction of 8−10 k B T at room temperature. This accounts for the long-range alignment of the crystal planes of individual nanocrystals in self-assembled superstructures and for anisotropic nanostructures grown via oriented attachment.

Electrons can be injected into TiO2 nanocrystals by a surface-adsorbed Ru-based dye in a well-known photosensitization process. Here we present time-resolved microwave conductivity measurements of the decay of electrons out of an electrically interconnected network of such TiO2 nanocrystals, following charge injection, and in the presence of an electron donor to the dye cation that prevents direct recombination. The time scale for this decay process is hundreds of milliseconds to seconds and explains the high current collection efficiency in devices based on these materials, since the long time scale allows for slow charge transport through the network.

The Bethe-Salpeter equation for coupled-channel N-b scattering is extended to satisfy unitarity in the NN and NN~sectors. The procedure eliminates the unitarity violations characteristic of the standard ladder Bethe-Salpeter equation in the inelastic region, and improves the description of pion production near threshold. Results are presented for the NN phase shifts and a number of observables up to 1 GeV. In particular, the D2 inelasticity is found to be considerably smaller than found from phase shift analysis. In this context, the importance of the pion deuteron channel for the inelasticity parameter is pointed out.