Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy

Glomerulosclerosis of any cause is characterized by loss of functional glomerular cells and deposition of excessive amounts of interstitial collagens including collagen I. We have previously reported that mesangial cell attachment to collagen I leads to upregulation of Hic-5 in vitro, which mediates mesangial cell apoptosis. Furthermore, glomerular Hic-5 expression was increased during the progression of experimental glomerulosclerosis. We hypothesized that reducing collagen I accumulation in glomerulosclerosis would in turn lower Hic-5 expression, reducing mesangial cell apoptosis, and thus maintaining glomerular integrity. We examined archive renal tissue from rats undergoing experimental diabetic glomerulosclerosis, treated with the transglutaminase-2 inhibitor NTU281. Untreated animals exhibited increased glomerular collagen I accumulation, associated with increased glomerular Hic-5 expression, apoptosis, and mesangial myofibroblast transdifferentiation characterized by a-smooth muscle actin (a-SMA) expression. NTU281 treatment reduced glomerular collagen I accumulation, Hic-5 and a-SMA expression, and apoptosis. Proteinurea and serum creatinine levels were significantly reduced in animals with reduced Hic-5 expression. In vitro studies of Hic-5 knockdown or overexpression show that mesangial cell apoptosis and expression of both a-SMA and collagen I are Hic-5 dependent. Together, these data suggest that there exists, in vitro and in vivo, a positive feedback loop whereby increased levels of collagen I lead to increased mesangial Hic-5 expression favoring not only increased apoptosis, but also mesangial myofibroblast transdifferentiation and increased collagen I expression. Prevention of collagen I accumulation interrupts this Hic-5-dependent positive feedback loop, preserving glomerular architecture, cellular phenotype, and function. © 2013 USCAP, Inc All rights reserved.

Increases in renal ε-(γ-glutamyl)-lysine crosslinks result from compartment-specific changes in tissue transglutaminase in early experimental diabetic nephropathy:Pathologic implications

Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, e-(γ-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney e-(γ-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (+337%) and peaked at Day 120 (+650%) (p <0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p <0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular e-(γ-glutamyl) lysine (+ 361%); however, in the glomeruli this was associated with increases in Tg activity (+228%) and tTg antigen by Western blotting (+215%). Importantly, the ratio of glomerular e-(γ-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca2+ and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN.

Predator–prey naïveté, antipredator behavior, and the ecology of predator invasions

We present a framework for explaining variation in predator invasion success and predator impacts on native prey that integrates information about predator–prey naïveté, predator and prey behavioral responses to each other, consumptive and non-consumptive effects of predators on prey, and interacting effects of multiple species interactions. We begin with the ‘naïve prey’ hypothesis that posits that naïve, native prey that lack evolutionary history with non-native predators suffer heavy predation because they exhibit ineffective antipredator responses to novel predators. Not all naïve prey, however, show ineffective antipredator responses to novel predators. To explain variation in prey response to novel predators, we focus on the interaction between prey use of general versus specific cues and responses, and the functional similarity of non-native and native predators. Effective antipredator responses reduce predation rates (reduce consumptive effects of predators, CEs), but often also carry costs that result in non-consumptive effects (NCEs) of predators. We contrast expected CEs versus NCEs for non-native versus native predators, and discuss how differences in the relative magnitudes of CEs and NCEs might influence invasion dynamics. Going beyond the effects of naïve prey, we discuss how the ‘naïve prey’, ‘enemy release’ and ‘evolution of increased competitive ability’ (EICA) hypotheses are inter-related, and how the importance of all three might be mediated by prey and predator naïveté. These ideas hinge on the notion that non-native predators enjoy a ‘novelty advantage’ associated with the naïveté of native prey and top predators. However, non-native predators could instead suffer from a novelty disadvantage because they are also naïve to their new prey and potential predators. We hypothesize that patterns of community similarity and evolution might explain the variation in novelty advantage that can underlie variation in invasion outcomes. Finally, we discuss management implications of our framework, including suggestions for managing invasive predators, predator reintroductions and biological control.

Lender Liability: The Legal and Management Effects on the Hospitality Industry

With the savings and loan crisis and the tail end of a recession at hand, the '90s are bound to be a difficult decade for the financing of hospitality operations through borrowing from commercial lenders. The authors discuss one of the least known dangers associated with borrowing, lender liability. The issue is discussed from both a legal and managerial perspective.

Sedimentology of various cores from the West Antarctic continental margin

Three megascopic and disseminated tephra layers (which we refer to as layers A, B, and C) occur in late Quaternary glaciomarine sediments deposited on the West Antarctic continental margin. The stratigraphical positions of the distal tephra layers in 28 of the 32 studied sediment cores suggest their deposition during latest Marine Isotopic Stage (MIS) 6 and MIS 5. One prominent tephra layer (layer B), which was deposited subsequent to the penultimate deglaciation (Termination II), is present in almost all of the cores. Geochemical analyses carried out on the glass shards of the layers reveal a uniform trachytic composition and indicate Marie Byrd Land (MBL), West Antarctica, as the common volcanic source. The geochemical composition of the marine tephra is compared to that of ash layers of similar age described from Mount Moulton and Mount Takahe in MBL and from ice cores drilled at Dome Fuji, Vostok and EPICA Dome C in East Antarctica. The three tephra layers in the marine sediments are chemically indistinguishable. Also five englacial ash layers from Mt. Moulton, which originated from highly explosive Plinian eruptions of the Mt. Berlin volcano in MBL between 142 ka and 92 ka ago, are chemically very similar, as are two tephra layers erupted from Mt. Takahe at ca. 102 ka and ca. 93 ka. Statistical analysis of the chemical composition of the glass shards indicates that the youngest tephra (layer A) in the marine cores matches the ash layer erupted from Mt. Berlin at 92 ka, which was previously correlated with tephra layers in the EPICA Dome C and the Dome Fuji ice cores. A tephra erupted from Mt. Berlin at 136 ka seems to correspond to a tephra layer deposited at 1733 m in the EPICA Dome C ice core. Additionally, the oldest tephra (layer C) in the marine sediments resembles an ash layer deposited at Vostok around 142 ka, but statistical evidence for the validity of this correlation is inconclusive. Although our results underscore the potential of tephrostratigraphy for correlating terrestrial and marine palaeoclimate archives, our study also reveals limitations of this technique, which may result in the miscorrelation of tephra. Such pitfalls comprise failure to recognise the occurrence of various tephra layers in marine sediment cores, 'swamping' of records with chemically indistinguishable tephra from a single volcanic source, and exclusive use of 'geochemical fingerprinting' for correlating ash layers.

(Table 1, page 171) Thorium and cobalt content of the total aggregate of manganese nodules from various locations

A criterion is suggested for discrimination between ferromanganese oxide minerals, deposited after the introduction of manganese and associated elements in sea water solution at submarine vulcanism, and minerals which are slowly formed from dilute solution, largely of continental origin. The simlultaneous injection of thorium into the ocean by submarine vulcanism is indicated, and its differentiation from continental thorium introduced into the ocean by runoff is discussed.