Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARα or PPARγ ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARα or PPARγ antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARα and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARα and PPARγ enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARα and PPARγ agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARγ agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARα/γ and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired

Potentiality of feed-forward neural networks for classifying dark formations to oil spills and look-alikes

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Molecular statics simulation of nanoindentation using adaptive quasicontinuum method

In this work, molecular statics is used to model a nanoindentation test on a two-dimensional hexagonal lattice. To this end, the QuasiContinuum (QC) method with adaptive propagation of the fully resolved domain is used to reduce the computational cost required by the full atomistic model. Three different adaptive mesh refinement criteria are introduced and tested, based on: (i) the Zienkiewicz-Zhu criterion (used for the deformation gradient), (ii) local atoms’ site energy, and (iii) local lattice disregistry. Accuracy and efficiency of individual refinement schemes are compared against the full atomistic model and obtained results are discussed

Molecular statics simulation of dislocation pileup using quasicontinuum method

In this contribution, accuracy of the QuasiContinuum (QC) methodology is studied for the case of dislocation pileup against an impenetrable obstacle in two-dimensional hexagonal lattices. To this end, a simplified shear test with a predetermined horizontal glide plane and next-to-nearest interactions described by the Lennard-Jones potential is adopted. The full molecular statics solution is computed, which is compared to two different QC simulations in terms of spatial positioning of individual dislocations along the glide plane, corresponding disregistry profiles, and dislocation core structures