Blocking TGF-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of PDGFRβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats

The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation

Cutibacterium acnes protects Candida albicans from the effect of micafungin in biofilms

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Influence of preservation temperature on endothelial cells and kidney phenotypes

Introduction: Ischemia reperfusion (IR) injury is unavoidable during organ transplantation and leads to complications. With the increased use of marginal donors, more sensitive to IR, solutions must be found to improve outcome. We hypothesized that a higher preservation temperature could offer better protection against IR.[br/]Methods: We tested this in an in vitro model of IR using primary endothelial cells and in ex vivo preserved pig kidneys. In both, 24 h preservation in University of Wisconsin solution was used.[br/]Results: In vitro, compared to 4°C, temperatures between 19 and 32°C provided higher protection against cell death (LDH release test), permitting better mitochondrial function (complexes II and V activity tests) and a lowerexpression of endothelial activation and inflammation markers TLR4, MCP1 and ICAM1. Ex vivo, however, the superiority of 19 or 32°C was lost, as preserved pig kidneys showed similar levels of tissue damage (both tubulardilatation, loss of brush border and endoluminal detachment) during preservation, and at 24 h the 4°C kidneys displayed a trend towards less damage. In addition, the tissular Monocyte/Macrophage infiltration was increased in the 19°C and more in the 32°C temperature conservation as compared to 4°C storage.[br/]Conclusion: Our study shows that although a higher preservation temperature is preferable for cell survival and function, whole organ testing demonstrates that conceptual work needs to be performed to harness the potential of sub-normothermia

Activity of Six Essential Oils Extracted from Tunisian Plants against Legionella pneumophila

International audienceThe aim of this study was to investigate the composition of six essential oils extracted from Tunisian plants, i.e., Artemisia herba-alba Asso, Citrus sinensis (L.) Osbeck, Juniperus phoenicea L., Rosmarinus officinalis L., Ruta graveolens L., and Thymus vulgaris L., and to evaluate their activity against Legionella pneumophila (microdilution assays). Eight Legionella pneumophila strains were studied, including the two well-known serogroup 1 Lens and Paris strains as controls and six environmental strains isolated from Tunisian spas belonging to serogroups 1, 4, 5, 6, and 8. The essential oils were generally active against L. pneumophila. The activities of the A. herba-alba, C. sinensis, and R. officinalis essential oils were strain-dependent, whereas those of the J. phoenicea and T. vulgaris oils, showing the highest anti-Legionella activities, with minimum inhibitory concentrations (MICs) lower than 0.03 and lower than or equal to 0.07 mg/ml, respectively, were independent of the strains' serogroup. Moreover, the microorganisms treated with T. vulgaris essential oil were shorter, swollen, and less electron-dense compared to the untreated controls. Isoborneol (20.91%), (1S)-α-pinene (18.30%) β-phellandrene (8.08%), α-campholenal (7.91%), and α-phellandrene (7.58%) were the major components isolated from the J. phoenicea oil, while carvacrol (88.50%) was the main compound of the T. vulgaris oil, followed by p-cymene (7.86%). This study highlighted the potential interest of some essential oils extracted from Tunisian plants as biocides to prevent the Legionella risk

Le probenecid prévient la nécrose tubulaire aiguë et la fibrose interstitielle dans un modèle murin de la néphropathie aux acides aristolochiques

Introduction.– La néphropathie aux acides aristolochiques (NAA) se caractérise par des lésions tubulo-interstitielles (TI) précoces (nécrose tubulaire et infiltrat inflammatoire) et tardives (atrophie tubulaire et fibrose interstitielle). In vitro, le probenecid (PBN), inhibe l’entrée des AA via les transporteurs d’anions organiques (TAO) 1–4, réduit la formation des adduits d’ADN spécifiques aux AA et préserve la viabilité cellulaire. Nous rapportons les effets fonctionnels et structurels de l’administration du PBN au cours de la NAA expérimentale.Patients et méthodes.– Quatre groupes de 24 souris C57BL/6 mâles ont reçu respectivement en intra-péritonéal :polyethylène glycol (PEG), solvant des AA ;PEG + PBN ;AA ou AA + PBN. Les AA (5 mg/kg) ou le volume équivalent de PEG ont été injectés 1 × /j et le PBN (150 mg/kg) 2 × /j. Six souris/groupe ont été sacrifiées après 2, 4, 5 et 8 jours d’injection. Le sang et le tissu rénal ont été prélevés. La créatininémie (Cr), l’histologie (microscopie optique et électronique (ME), le processus de réparation des dommages de l’ADN (immunomarquage du PCNA) ainsi que la quantification des adduits d’ADN spécifiques aux AA ont été évalués.Résultats.– Contrairement aux souris recevant PEG ou PEG + PBN, exemptes de toute anomalie fonctionnelle et structurelle, les AA provoquent une insuffisance rénale aiguë secondaire à une nécrose des cellules tubulaires proximales (CTP) observée dans les segments S3 (jours 4-5). Un infiltrat inflammatoire mononucléé associé à une atrophie tubulaire et une fibrose interstitielle ont été observés au jour 8. Aucune élévation de la créatininémie n’a été mesurée dans le groupe AA + PBN. Dès le jour 5, les scores d’atteintes TI ont été significativement réduits ainsi que le nombre de cellules PCNA+. La quantité d’adduits d’ADN totaux a été significativement réduite au jour 8. En ME, la sévérité et l’étendue des lésions ultrastructurales induites par les AA (perte de la bordure en brosse, œdème mitochondrial et effacement des crêtes des mitochondries) ont été nettement diminuées par le PBN (voir la figure en bas de la page).Évolution de la créatininémie, du score d’atteinte TI et de la quantité d’adduits d’ADN dans le groupe AA (colonnes blanches) et le groupe AA + PBN (colonnes grises). Les valeurs sont des moyennes + - ESM, (n = 6/groupe) ;**p < 0,01.Discussion.– Le PBN, en inhibant les TAO, réduit probablement l’intoxication des CTP par les AA, ce qui contribue à une diminution des lésions mitochondriales et de la formation des adduits d’ADN.Conclusion.– Notre étude démontre pour la 1e fois l’effet néphroprotecteur du PBN vis-à-vis de la tubulotoxicité aiguë et de la fibrose interstitielle induites par les AA dans le modèle murin de la NAA.Communication orale à la XIIIe Reunion commune de la Societe Francophone de Dialyse (SFD) et de la Societe de Nephrologie (SN) le mercredi 5 octobre 2011, Bordeaux (Palais des Congrès), lors de la session "Concours des internes". Communication CI01.info:eu-repo/semantics/publishe

Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice

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Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy

Communication au XLIV Annual Meeting of the American Society of Nephrology (Philadelphia, USA, 2011)info:eu-repo/semantics/publishe

Effet protective du probenecid sur l'atteinte tubulo-interstitielle aigue dans le model de la nephropathie aux acides aristolochiques

info:eu-repo/semantics/publishedAbstract de la 13ème réunion commune de la Société de néphrologie et de la Société francophone de dialyse (Bardeaux, septembre 2011

Probenecid prevents acute tubular necrosis and interstitial fibrosis in a mouse model of aristolochic acid nephropathy

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Fanconi syndrome and chronic kidney disease in paroxysmal nocturnal hemoglobinuria: effect of eculizumab therapy.

International audienceThe association of Fanconi syndrome (FS) and chronic kidney disease (CKD) has been rarely described during the course of paroxysmal nocturnal hemoglobinuria (PNH). We report 2 patients with PNH and CKD associated with proximal tubule dysfunction, which manifested as full-blown FS in one case. In both patients, abnormal iron load within the kidneys was demonstrated by magnetic resonance imaging, which correlated with diffuse and numerous hemosiderin inclusions within proximal tubular cells. After 12 months, eculizumab treatment resulted in significant decrease in the kidney iron load in both cases. Glomerular filtration rate improved in one case and was stabilized in the other, in whom pretreatment kidney biopsy had shown severe extensive interstitial fibrosis. However, symptoms of proximal tubular dysfunction persisted in both patients. These data suggest that hemosiderin deposition in proximal tubules is probably an important mechanism involved in the development of FS, an under recognized and early manifestation of CKD in PNH. Prolonged treatment with eculizumab may improve long-term renal function in PNH patients with CKD