Renal disease pathophysiology and treatment:contributions from the rat

The rat has classically been the species of choice for pharmacological studies and disease modeling, providing a source of high-quality physiological data on cardiovascular and renal pathophysiology over many decades. Recent developments in genome engineering now allow us to capitalize on the wealth of knowledge acquired over the last century. Here, we review rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of renal diseases and have revealed key genes, such as Ace and P2rx7, involved in renal pathogenic processes. By targeting these genes of interest, researchers are gaining a better understanding of the etiology of renal pathologies, with the promised potential of slowing disease progression or even reversing the damage caused. Some, but not all, of these target genes have proved to be of clinical relevance. However, it is now possible to generate more sophisticated and appropriate disease models in the rat, which can recapitulate key aspects of human renal pathology. These advances will ultimately be used to identify new treatments and therapeutic targets of much greater clinical relevance

Transcription controls growth, cell kinetics and cholesterol supply to sustain ACTH responses

Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P < 0.001; 397 up, 531 down). These clustered in pathways involved in signalling, sterol/lipid metabolism, cell proliferation/hypertrophy and apoptosis. Signalling genes included some implicated in adrenal adenomas but also upregulated genes associated with cyclic AMP and downregulated genes associated with aldosterone synthesis. Sterol metabolism genes were those promoting cholesterol supply (Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P < 0.05; <1.3-fold). Increased Ki67, Ccna2, Ccnb2 and Tk1 expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P < 0.001) and more widely distributed throughout the cortex. In summary, long-term steroidogenesis with ACTH excess is sustained by genes controlling cholesterol supply and adrenal mass. ACTH effects on adrenal morphology and genes controlling cell hypertrophy, proliferation and apoptosis suggest the involvement of different cell types and separate molecular pathways

Early stages of ramified growth in quasi-two-dimensional electrochemical deposition

I have measured the early stages of the growth of branched metal aggregates formed by electrochemical deposition in very thin layers. The growth rate of spatial Fourier modes is described qualitatively by the results of a linear stability analysis [D.P. Barkey, R.H. Muller, and C.W. Tobias, J. Electrochem. Soc. {\bf 136}, 2207 (1989)]. The maximum growth rate is proportional to $(I/c)^\delta$ where $I$ is the current through the electrochemical cell, $c$ the electrolyte concentration, and $\delta = 1.37 \pm 0.08$. Differences between my results and the theoretical predictions suggest that electroconvection in the electrolyte has a large influence on the instability leading to ramified growth.Comment: REVTeX, four ps figure

Permanent annihilation of thermally activated defects which limit the lifetime of float-zone silicon

We have observed very large changes in the minority carrier lifetime when high purity float-zone (FZ) silicon wafers are subject to heat-treatments in the range of 200– 1100˚C. Recombination centres were found to become activated upon annealing at 450–700˚C, causing significant reductions in the bulk lifetime, detrimental for high efficiency solar cells and stable high powered devices. Photoluminescence imaging of wafers annealed at 500˚C revealed concentric circular patterns, with lower lifetimes occurring in the centre, and higher lifetimes around the periphery. Deep level transient spectroscopy measurements on samples extracted from the centre of an n-type FZ silicon wafer annealed at 500˚C revealed a large variety of defects with activation energies ranging between 0.16– 0.36eV. Our measurements indicate that vacancy related defects are causing the severe degradation in lifetime when FZ wafers are annealed at 450–700˚C. Upon annealing FZ silicon at temperatures >800°C, the lifetime is completely recovered, whereby the defect-rich regions vanish and do not reappear (permanently annihilated). Our results indicate that, in general, as-grown FZ silicon should not be assumed to be defect lean, nor can it be assumed that the bulk lifetime will remain stable during thermal processing, unless annealed at temperatures >1000°C

Evaluation of variants in the selectin genes in age-related macular degeneration

<p>Abstract</p> <p>Background</p> <p>Age-related macular degeneration (AMD) is a common disease of the elderly that leads to loss of the central visual field due to atrophic or neovascular events. Evidence from human eyes and animal models suggests an important role for macrophages and endothelial cell activation in the pathogenesis of AMD. We sought to determine whether common ancestral variants in genes encoding the selectin family of proteins are associated with AMD.</p> <p>Methods</p> <p>Expression of E-selectin, L-selectin and P-selectin was examined in choroid and retina by quantitative PCR and immunofluorescence. Samples from patients with AMD (n = 341) and controls (n = 400) were genotyped at a total of 34 SNPs in the <it>SELE</it>, <it>SELL </it>and <it>SELP </it>genes. Allele and genotype frequencies at these SNPs were compared between AMD patients and controls as well as between subtypes of AMD (dry, geographic atrophy, and wet) and controls.</p> <p>Results</p> <p>High expression of all three selectin genes was observed in the choroid as compared to the retina. Some selectin labeling of retinal microglia, drusen cores and the choroidal vasculature was observed. In the genetic screen of AMD versus controls, no positive associations were observed for <it>SELE </it>or <it>SELL</it>. One SNP in <it>SELP </it>(rs3917751) produced p-values < 0.05 (uncorrected for multiple measures). In the subtype analyses, 6 SNPs (one in <it>SELE</it>, two in <it>SELL</it>, and three in <it>SELP</it>) produced p-values < 0.05. However, when adjusted for multiple measures with a Bonferroni correction, only one SNP in <it>SELP </it>(rs3917751) produced a statistically significant p-value (p = 0.0029).</p> <p>Conclusions</p> <p>This genetic screen did not detect any SNPs that were highly associated with AMD affection status overall. However, subtype analysis showed that a single SNP located within an intron of <it>SELP </it>(rs3917751) is statistically associated with dry AMD in our cohort. Future studies with additional cohorts and functional assays will clarify the biological significance of this discovery. Based on our findings, it is unlikely that common ancestral variants in the other selectin genes (<it>SELE </it>and <it>SELL</it>) are risk factors for AMD. Finally, it remains possible that sporadic or rare mutations in <it>SELE</it>, <it>SELL</it>, or <it>SELP </it>have a role in the pathogenesis of AMD.</p

Identification of a human ortholog of the mouse Dcpp gene locus, encoding a novel member of the CSP-1/Dcpp salivary protein family

Glycolaldehyde is a key molecule in the formation of biologically relevant molecules such as ribose. We report its detection with the Plateau de Bure interferometer towards the Class 0 young stellar object NGC1333 IRAS2A, which is only the second solar-type protostar for which this prebiotic molecule is detected. Local thermodynamic equilibrium analyses of glycolaldehyde, ethylene glycol (the reduced alcohol of glycolaldehyde) and methyl formate (the most abundant isomer of glycolaldehyde) were carried out. The relative abundance of ethylene glycol to glycolaldehyde is found to be ~5 -higher than in the Class 0 source IRAS 16293-2422 (~1), but comparable to the lower limits derived in comets ($\geq$3-6). The different ethylene glycol-to-glycolaldehyde ratios in the two protostars could be related to different CH3OH:CO compositions of the icy grain mantles. In particular, a more efficient hydrogenation on the grains in NGC 1333 IRAS2A would favor the formation of both methanol and ethylene glycol. In conclusion, it is possible that, like NGC 1333 IRAS2A, other low-mass protostars show high ethylene glycol-to-glycolaldehyde abundance ratios. The cometary ratios could consequently be inherited from earlier stages of star formation, if the young Sun experienced conditions similar to NGC1333 IRAS2A.Comment: 11 pages, 5 figures, accepted in A&

Recombination via transition metals in solar silicon : the significance of hydrogen-metal reactions and lattice sites of metal atoms

The move towards lower cost sources of solar silicon has intensified efforts to investigate the possibilities of passivating or reducing the recombination activity caused by deep states associated with transition metals. This is particularly important for the case of the slow diffusing metals early in the periodic sequence which are not removed by conventional gettering. In this paper we examine reactions between hydrogen and transition metals and discuss the possibility of such reactions during cell processing. We analyse the case of hydrogenation of iron in p-type Si and show that FeH can form under non-equilibrium conditions. We consider the electrical activity of the slow diffusing metals Ti, V and Mo, how this is affected in the presence of hydrogen, and the stability of TM-H complexes formed. Finally we discuss recent experiments which indicate that resiting of some transition metals from the interstitial to substitutional site is possible in the presence of excess vacancies, leading to a reduction in recombination activity

Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2

Deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11β-HSD2 gene. Homozygous mutant mice (11β-HSD2(–/–)) appear normal at birth, but ∼50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11β-HSD2(–/–) mice are markedly hypertensive, with a mean arterial blood pressure of 146 ± 2 mmHg, compared with 121 ± 2 mmHg in wild-type controls and 114 ± 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11β-HSD2(–/–) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension. J. Clin. Invest. 103:683–689 (1999