Lawson WE, Gow AJ, Harris RC, Dikov MM, Tchekneva EE. Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress. Am J Physiol Renal Physiol 304: F1295-F1307, 2013. First published March 13, 2013 doi:10.1152/ajprenal.00344.2012.-Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules. proximal tubules; acute kidney injury; protein oligomerization.
The development of new admixtures for concrete is normally an experimental endeavor in that the molecular scaffolds of existing admixtures are modified and tested. This approach is time consuming, incremental and typically expensive. Alternatively, a computer‐aided molecular design (CAMD) approach is proposed that uses the Signature molecular descriptor. CAMD is the application of computer‐implemented algorithms that are utilized to design molecules with optimally predicted properties such that they can be tested and evaluated for efficacy. The property of interest here is the surface tension of compounds in aqueous solutions as this property is related to shrinkage in concrete. In particular, we have chosen two classes of compounds, amines and glycol ethers, as they present opportunities for use as shrinkage reducing admixtures (SRAs). By evaluating the initial surface tension reduction in these compounds in solution with water, a number of structure–property conjectures associated with the effect of these compounds were developed. From these conjectures, 14 compounds were identified and utilized as a training set for the CAMD of new compounds. After creating and refining a quantitative structure–property relationship (QSPR) model for surface tension reduction, a structure enumeration algorithm was employed to generate structures outside of the original training set that have optimally predicted properties. In work, the CAMD approach is introduced as well as the identification of new compounds with the greatest predicted impact on the surface tension reduction in water. Furthermore, the surface tension reduction for the newly identified compounds was experimentally evaluated.
In this study, the use of computer-aided molecular design (CAMD) is validated as a tool for enabling the discovery of new shrinkage-reducing compounds for possible use in portland cement composites and is framed as one of many multiscale modeling tools in a broad hierarchy of possibilities. Twelve additives were tested for their ability to inhibit shrinkage in Type I ordinary portland cement under both autogenous and drying conditions. The 12 additives included two commercial shrinkage-reducing admixtures (SRAs), two active ingredients of a commercial admixture [one of which was used to establish the quantitative structure-property relationships (QSPR)], two additional classified as potential SRA compounds based on the patent literature, four newly identified compounds predicted by using CAMD and an inverse quantitative structure-property relationship (I-QSPR), and two other compounds use to establish the QSPR relationship. The newly identified I-QSPR compounds were targeted for their ability to reduce the surface tension of water, a primary consideration for shrinkage-reducing activity. Results for both drying shrinkage and autogenous shrinkage indicate that the designed compounds perform similar to commercial admixtures, yet have different chemical functionalities. Hydration data and set measurements were also considered since selection of new SRAs is a multiparameter problem with many constraints. Thus, these newly identified shrinkage-reducing compounds can potentially provide additional options for use in portland cement concrete applications.
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