Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production

Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice.This study was supported by RETICS 06/0016 (VFM, RS) and FIS PI 09/0064 (RS) from the Fondo de Investigaciones Sanitarias (Health Research Fund). MLC was funded by SAF 2013-47611-R, SAF 2010-21249, and SAF 2007-61201 from the Ministerio de Economía y competitividad. MRO was supported by RETICS 12/0021,S2012DMD2321 from the Comunidad Autónoma de Madrid, PI 11/01854 from Fondo Investigaciones Sanitarias. GTGM was supported by Renal Foundation Íñigo Álvarez de Toledo, FIBHULP, and by Severo Ochoa FoundationPeer Reviewe

Searching for inhibition of return in the rat using the covert orienting of attention task

Inhibition of return (IOR) is an important psychological construct describing inhibited responses to previously attended locations. In humans, it is investigated using Posner’s cueing paradigm. This paradigm requires central visual fixation and detection of cued stimuli to the left or right of the fixation point. Stimuli can be validly or invalidly cued, appearing in the same or opposite location to the cue. Although a rat version of the spatial cueing paradigm (the covert orienting of attention task) does exist, IOR has so far not been demonstrated. We therefore investigated whether IOR could be robustly demonstrated in adult male rats using the covert orienting of attention task. This task is conducted in holed wall operant chambers with the central three holes mimicking the set-up for Posner cueing. Across four samples of rats (overall n = 84), we manipulated the following task parameters: stimulus onset asynchronies (Experiments 1–3), cue brightness (Experiment 1b) and the presence of a central reorienting event (Experiment 4). In Experiment 1, we also investigated strain differences by comparing Lister Hooded rats to Sprague–Dawley rats. Although Lister Hooded rats briefly showed evidence of IOR (Experiment 1a, and see Online Resource 1 data), we were unable to replicate this finding in our other experiments using different samples of this strain. Taken together, our findings suggest that IOR cannot be robustly demonstrated in the rat using the covert orienting of attention task conducted in holed wall operant chambers