Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)

Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the effect of the mTOR inhibitor sirolimus (rapamycin) on renal functional loss and cyst progression in the Han:SPRD rat model of ADPKD. Methods. Five-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) rats were administered sirolimus (2 mg/kg/day) orally through the drinking water for 3 months. The renal function was monitored throughout the treatment phase, and rats were sacrificed thereafter. Kidneys were analysed histomorphometrically, and for the expression and phosphorylation of S6K, a well-characterized target of mTOR in the regulation of cell growth. Results. The steady increase in BUN and creatinine in Cy/+ rats was reduced by 39 and 34%, respectively with sirolimus after 3 months treatment. Kidney weight and 2-kidney/total body weight (2K/TBW) ratios were reduced by 34 and 26% in sirolimus-treated Cy/+ rats. Cyst volume density was also reduced by 18%. Of importance, Cy/+ rats displayed enhanced levels of total and phosphorylated S6K. Sirolimus effectively reduced total and phosphorylated levels of S6K. Conclusion. We conclude that oral sirolimus markedly delays the loss of renal function and retards cyst development in Han:SPRD rats with ADPKD. Our data also suggest that activation of the S6K signalling pathway plays an important role in the pathogenesis of PKD. Sirolimus could be a useful drug to retard progressive renal failure in patients with ADPK

Residual transport model in correlation with sedimentary dynamics over an elongate tidal sandbar in the Gironde Estuary (Southwestern France)

This study qualitatively describes by a multidisciplinary approach hydrodynamic and residual sediment transport over a sandbar in a macrotidal environment. The sandbar is elongated and attached to a headland that is located in the Gironde estuary (southwestern France). Bathymetric surveys, side-scan-sonar sonograms, grain-size trends of surficial sediment, and 2DH numerical simulations of current patterns were used to define a conceptual model for the dynamics of this sandbar. The sandbar is oriented anticlockwise with respect to the main flow. The channel-oriented bar face is ebb-dominated, whereas the opposite face is flood-dominated, resulting in a clockwise residual transport. The line of sediment flux convergence corresponds to the crest of the bar. The residual flow over the bar appears to originate from the regional estuarine flow. The dominant process responsible for the maintenance of the sandbar seems to be the depth-averaged main tidal flow rather than secondary circulation due to headlands or the interaction between the tidal flow and the seabed. To generalize this regional conceptual model a qualitative comparison is made with the theories of sandbar dynamics due to tidal currents (Pingree and Maddock 1979, Zimmerman 1981, Huthnance 1982, and others). The seabed stability approach developed by Huthnance (1982) seems to be the most reliable theory to explain the Saint-Georges Bank dynamics, even though many natural factors are not taken into account

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease

Background. Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kidney disease. We hypothesized that matrix and TBM degradation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment on MMPs. Methods. 5-week-old male heterozygous (Cy/+) and wild-type normal (+/+) rats were treated with sirolimus (2 mg/kg/day) through drinking water for 3 months. Results. The mRNA and protein levels of MMP-2 and MMP-14 were markedly increased in the kidneys of heterozygous Cy/+ animals compared to wild-type +/+ as shown by RT-PCR and Western blot analyses for MMP-2 and MMP-14, and by zymography for MMP-2. Strong MMP-2 expression was detected by immunoperoxidase staining in cystic epithelial cells that also displayed an altered, thickened TBM. Tissue inhibitor of metalloproteinases-2 (TIMP-2) expression was not changed in Cy/+ kidneys. Sirolimus treatment leads to decreased protein expression of MMP-2 and MMP-14 in Cy/+, whereas MMP-2 and MMP-14 mRNA levels and TIMP-2 protein levels were not affected by sirolimus. Conclusion. In summary, in kidneys of the Han:SPRD rat model of ADPKD, there is a marked upregulation of MMP-2 and MMP-14. Sirolimus treatment was associated with a marked improvement of MMP-2 and MMP-14 overexpression, and this correlated also with less matrix and TBM alterations and milder cystic diseas

Utilisation of numerical and statistical techniques to describe sedimentary circulation patterns in the mouth of the Gironde estuary

Sediment distribution is well defined in the mouth of the Gironde estuary but the sediment dynamics is still poorly understood. The aim of this work is to analyse residual circulation of non-cohesive sediment due to the action of the main hydrodynamic factor: tidal currents. A depth-averaged numerical model emphasises the residual circulation of the Gironde estuary, which is characterised by residual tidal gyres. The comparison between sediment transport calculated from the numerical model and from a statistical analysis of the sedimentary distribution leads to the definition of a simple scheme of non-cohesive sediment circulation in the Gironde estuary’s mouth

The renal cortical interstitium: morphological and functional aspects

The renal interstitial compartment, situated between basement membranes of epithelia and vessels, contains two contiguous cellular networks. One network is formed by interstitial fibroblasts, the second one by dendritic cells. Both are in intimate contact with each other. Fibroblasts are interconnected by junctions and connected to basement membranes of vessels and tubules by focal adhesions. Fibroblasts constitute the “skeleton” of the kidney. In the renal cortex, fibroblasts produce erythropoietin and are distinguished from other interstitial cells by their prominent F-actin cytoskeleton, abundance of rough endoplasmic reticulum, and by ecto-5′-nucleotidase expression in their plasma membrane. The resident dendritic cells belong to the mononuclear phagocyte system and fulfil a sentinel function. They are characterized by their expression of MHC class II and CD11c. The central situation of fibroblasts suggests that signals from tubules, vessels, and inflammatory cells converge in fibroblasts and elicit an integrated response. Following tubular damage and inflammatory signals fibroblasts proliferate, change to the myofibroblast phenotype and increase their collagen production, potentially resulting in renal fibrosis. The acquisition of a profibrotic phenotype by fibroblasts in renal diseases is generally considered a main causal event in the progression of chronic renal failure. However, it might also be seen as a repair process

Orbitally forced ice sheet fluctuations during the Marinoan Snowball Earth glaciation

Two global glaciations occurred during the Neoproterozoic. Snowball Earth theory posits that these were terminated after millions of years of frigidity when initial warming from rising atmospheric CO2 concentrations was amplified by the reduction of ice cover and hence a reduction in planetary albedo. This scenario implies that most of the geological record of ice cover was deposited in a brief period of melt-back. However, deposits in low palaeo-latitudes show evidence of glacial–interglacial cycles. Here we analyse the sedimentology and oxygen and sulphur isotopic signatures of Marinoan Snowball glaciation deposits from Svalbard, in the Norwegian High Arctic. The deposits preserve a record of oscillations in glacier extent and hydrologic conditions under uniformly high atmospheric CO2 concentrations. We use simulations from a coupled three-dimensional ice sheet and atmospheric general circulation model to show that such oscillations can be explained by orbital forcing in the late stages of a Snowball glaciation. The simulations suggest that while atmospheric CO2 concentrations were rising, but not yet at the threshold required for complete melt-back, the ice sheets would have been sensitive to orbital forcing. We conclude that a similar dynamic can potentially explain the complex successions observed at other localities

Interaction of eukaryotic translation initiation factor 4G with the nuclear cap-binding complex provides a link between nuclear and cytoplasmic functions of the m7 guanosine cap

In eukaryotes the majority of mRNAs have an m7G cap that is added cotranscriptionally and that plays an important role in many aspects of mRNA metabolism. The nuclear cap-binding complex (CBC; consisting of CBP20 and CBP80) mediates the stimulatory functions of the cap in pre-mRNA splicing, 3' end formation, and U snRNA export. As little is known about how nuclear CBC mediates the effects of the cap in higher eukaryotes, we have characterized proteins that interact with CBC in HeLa cell nuclear extracts as potential mediators of its function. Using cross-linking and coimmunoprecipitation, we show that eukaryotic translation initiation factor 4G (eIF4G), in addition to its function in the cytoplasm, is a nuclear CBC-interacting protein. We demonstrate that eIF4G interacts with CBC in vitro and that, in addition to its cytoplasmic localization, there is a significant nuclear pool of eIF4G in mammalian cells in vivo. Immunoprecipitation experiments suggest that, in contrast to the cytoplasmic pool, much of the nuclear eIF4G is not associated with eIF4E (translation cap binding protein of eIF4F) but is associated with CBC. While eIF4G stably associates with spliceosomes in vitro and shows close association with spliceosomal snRNPs and splicing factors in vivo, depletion studies show that it does not participate directly in the splicing reaction. Taken together the data indicate that nuclear eIF4G may be recruited to pre-mRNAs via its interaction with CBC and accompanies the mRNA to the cytoplasm, facilitating the switching of CBC for eIF4F. This may provide a mechanism to couple nuclear and cytoplasmic functions of the mRNA cap structure

Cenozoic evolution of the steppe-desert biome in Central Asia

The origins and development of the arid and highly seasonal steppe-desert biome in Central Asia, the largest of its kind in the world, remain largely unconstrained by existing records. It is unclear how Cenozoic climatic, geological, and biological forces, acting at diverse spatial and temporal scales, shaped Central Asian ecosystems through time. Our synthesis shows that the Central Asian steppe-desert has existed since at least Eocene times but experienced no less than two regime shifts, one at the Eocene–Oligocene Transition and one in the mid-Miocene. These shifts separated three successive “stable states,” each characterized by unique floral and faunal structures. Past responses to disturbance in the Asian steppe-desert imply that modern ecosystems are unlikely to recover their present structures and diversity if forced into a new regime. This is of concern for Asian steppes today, which are being modified for human use and lost to desertification at unprecedented rates

Clinical pharmacology of exogenously administered alkaline phosphatase

Purpose: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). Methods: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg-124 h-1) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. Results: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. Conclusions: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis