Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model.

BACKGROUND: Long-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown. MATERIALS AND METHODS: In a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation. RESULTS: Daily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4+ IL-17+ cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFß1, TNFα, INFγ, and MIP-1ß were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS. CONCLUSION: Development of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4+ IL-17+ cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.

A Novel Mouse Model of Peritoneal Dialysis: Combination of Uraemia and Long-Term Exposure to PD Fluid.

Different animal models for peritoneal dialysis (PD) have been used in the past decades to develop PD fluids compatible with patient life and to identify markers of peritoneal fibrosis and inflammation. Only few of those studies have taken into account the importance of uraemia-induced alterations at both systemic and peritoneal levels. Moreover, some animal studies which have reported about PD in a uremic setting did not always entirely succeed in terms of uraemia establishment and animal survival. In the present study we induced uraemia in the recently established mouse PD exposure model in order to obtain a more clinically relevant mouse model for kidney patients. This new designed model reflected both the slight thickening of peritoneal membrane induced by uraemia and the significant extracellular matrix deposition due to daily PD fluid instillation. In addition the model offers the opportunity to perform long-term exposure to PD fluids, as it is observed in the clinical setting, and gives the advantage to knock out candidate markers for driving peritoneal inflammatory mechanisms.

Sex steroids and their involvement in the cortisol-induced inhibition of pubertal development in male common carp, Cyprinus carpio L.

The onset and regulation of puberty is determined by functional development of the brain-pituitary-gonad (BPG) axis. Sex steroids produced in the gonads play an important role in the onset of puberty. Stress interferes with reproduction and the functioning of the BPG axis, and cortisol has frequently been indicated as a major factor mediating the suppressive effect of stress on reproduction. Prolonged elevated cortisol levels, implicated in stress adaptation, inhibited pubertal development in male common carp (Cyprinus carpio). Cortisol treatment caused a retardation of pubertal testis development and reduced the LH pituitary content and the salmon GnRHa-stimulated LH secretion in vitro. A reduced synthesis of androgens also was observed. These findings suggest that the cortisol-induced inhibition of testicular development and the maturation of pituitary gonadotrophs are mediated by an effect on testicular androgen secretion. In this study, we combined cortisol treatment with a replacement of the testicular steroid hormones (testosterone and 11-oxygenated androgens) to investigate the role of these steroids in the cortisol-induced suppression of pubertal development. The effect of cortisol on spermatogenesis was independent of 11-ketotestosterone, whereas the effect on the pituitary was an indirect one, involving the testicular secretion of testosterone.

Translational control of the Xenopus laevis connexin-41 5'-untranslated region by three upstream open reading frames.

The Xenopus laevis Connexin-41 (Cx41) mRNA contains three upstream open reading frames (uORFs) in the 5'-untranslated region (UTR). We analyzed the translation efficiency of constructs containing the Cx41 5'-UTR linked to the green fluorescent protein reporter after injection of transcripts into one-cell stage Xenopus embryos. The translational efficiency of the wild-type Cx41 5'-UTR was only 2% compared with that of the beta-globin 5'-UTR. Mutation of each of the three uAUGs into AAG codons enhanced translation 82-, 9-, and 4-fold compared with the wild-type Cx41 5'-UTR. Based on these increased translation efficiencies, the percentages of ribosomes that recognized the uAUGs were calculated. Only 0.03% of the ribosomes that entered at the cap structure scanned the entire 5'-UTR and translated the main ORF. The results indicate that all uAUGs are recognized by the majority of the scanning ribosomes and that the three uAUGs strongly modulate translation efficiency in Xenopus laevis embryos. Based on these data, a model of ribosomal flow along the mRNA is postulated. We conclude that the three uORFs may play an important role in the regulation of Cx41 expression.