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Van der Hauwaert C.,EA4483 | Savary G.,EA4483 | Gnemmi V.,French Institute of Health and Medical Research | Gnemmi V.,Lille 2 University of Health and Law | And 15 more authors.
PLoS ONE | Year: 2013

Renal proximal tubular epithelial cells play a central role in renal physiology and are among the cell types most sensitive to ischemia and xenobiotic nephrotoxicity. In order to investigate the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries, a stable and well-characterized primary culture model of proximal tubular cells is required. An existing model of proximal tubular cells is hampered by the cellular heterogeneity of kidney; a method based on cell sorting for specific markers must therefore be developed. In this study, we present a primary culture model based on the mechanical and enzymatic dissociation of healthy tissue obtained from nephrectomy specimens. Renal epithelial cells were sorted using co-labeling for CD10 and CD13, two renal proximal tubular epithelial markers, by flow cytometry. Their purity, phenotypic stability and functional properties were evaluated over several passages. Our results demonstrate that CD10/CD13 double-positive cells constitute a pure, functional and stable proximal tubular epithelial cell population that displays proximal tubule markers and epithelial characteristics over the long term, whereas cells positive for either CD10 or CD13 alone appear to be heterogeneous. In conclusion, this study describes a method for establishing a robust renal proximal tubular epithelial cell model suitable for further experimentation. © 2013 Van der Hauwaert et al.

Kroubi M.,EA4483 | Karembe H.,CEVA Sante Animale | Betbeder D.,EA4483
Expert Opinion on Drug Delivery | Year: 2011

Introduction: Animal African trypanosomiasis (AT) is treated and controlled with homidium, isometamidium and diminazene, whereas human AT is treated with suramin, pentamidine, melarsoprol and eflornithine (DFMO), or a combination of DFMO and Nifurtimox. Monotherapy can present serious side effects, for example, melarsoprol, the more frequently used drug that is effective for both hemolymphatic and meningoencephalic stages of the disease, is so toxic that it kills 5% of treated patients. These treatments are poorly efficient, have a narrow safety index and drug resistance is a growing concern. No new drug has been developed since the discovery of DFMO in the 1970s. There is a pressing need for an effective, safe drug for both stages of the disease, and recent research is focused on the development of new formulations in order to improve their therapeutic index. Areas covered: This review shows the potential interest of using nanoparticulate formulations of trypanocidal drug to improve parasite targeting, efficacy and, potentially, safety while being cost-effective. Expert opinion: The design of drug formulations relevant to the treatment of AT must include a combination of very specific properties. In summary, the drug delivery system must be compatible with the physicochemical properties of the drug (charge, lipophilicity and molecular mass) in order to allow high drug payloads while being biocompatible for the patient. © 2011 Informa UK, Ltd.

Glowacki F.,EA4483 | Savary G.,EA4483 | Gnemmi V.,French Institute of Health and Medical Research | Gnemmi V.,Institute Of Pathologie | And 15 more authors.
PLoS ONE | Year: 2013

MicroRNAs (miRNAs) are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA). Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001). By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), and between miR-21 levels and aMDRD (ß = -0.398, p = 0.006). Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis. © 2013 Glowacki et al.

Roy S.,RWTH Aachen | Benz F.,RWTH Aachen | Vargas Cardenas D.,RWTH Aachen | Vucur M.,RWTH Aachen | And 9 more authors.
Journal of Digestive Diseases | Year: 2015

Objective: MicroRNAs (miRNAs) have recently emerged as novel regulators in liver fibrosis. miR-30c and miR-193 are involved in fibrotic remodeling processes and cancer development, respectively. This study aimed to explore the role of miR-30c and miR-193 in liver fibrosis. Methods: The regulation of miRNAs in carbon tetrachloride-induced liver fibrosis was analyzed by microarray. Expression patterns of miR-193 and miR-30c were further confirmed in fibrotic liver samples obtained from two murine models of hepatic fibrosis and human tissues. On a functional level, miRNA levels were analyzed in the context of transforming growth factor (TGF-β) mediated activation of hepatic stellate cells (HSCs). Finally, predicted targets were assessed for their roles in fibrosis by transfecting murine HSCs with miRNA mimics. Results: Microarray analysis in murine fibrotic livers revealed a panel of 44 dysregulated miRNAs. In addition to previously established miRNAs known to be regulated in liver fibrosis in a TGF-β-dependent manner (e.g., miR-29, miR-133), miR-193 and miR-30c were observed to be specifically downregulated not only in experimental hepatofibrogenesis but also in human liver fibrosis, while they showed a reciprocal expression pattern after recovery from liver fibrosis. Functional experiments confirmed the TGF-β-dependent downregulation of these respective new miRNAs in HSCs. Finally, we identified TGF-β2 and SNAIL1, important regulators of extracellular matrix, as potential target genes of miR-193 and miR-30 in liver fibrosis. Conclusion: These results suggest that miR-30 and miR-193 are members of a network of miRNAs modifying the TGF-β-dependent regulation of extracellular matrix-related genes in HSCs in the manifestation and resolution of liver fibrosis. © 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Bertero T.,French National Center for Scientific Research | Bertero T.,University of Nice Sophia Antipolis | Robbe-Sermesant K.,French National Center for Scientific Research | Robbe-Sermesant K.,University of Nice Sophia Antipolis | And 13 more authors.
Antioxidants and Redox Signaling | Year: 2014

Significance: MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as key regulators of many physiological and pathological processes, including those relevant to hypoxia such as cancer, neurological dysfunctions, myocardial infarction, and lung diseases. Recent Advances: During the last 5 years, miRNAs have been shown to play a role in the regulation of the cellular response to hypoxia. The identification of several bona fide targets of these hypoxamiRs has underlined their pleiotropic functions and the complexity of the molecular rules directing miRNA::target transcript pairing. Critical Issues: This review outlines the main in silico and experimental approaches used to identify the targetome of hypoxamiRs and presents new recent relevant methodologies for future studies. Future Directions: Since hypoxia plays key roles in many pathophysiological conditions, the precise characterization of regulatory hypoxamiRs networks will be instrumental both at a fundamental level and for their future potential therapeutic applications. Antioxid. Redox Signal. 21, 1249-1268. © Mary Ann Liebert, Inc.

Lino Cardenas C.L.,EA4483 | Henaoui I.S.,French National Center for Scientific Research | Henaoui I.S.,University of Nice Sophia Antipolis | Courcot E.,EA4483 | And 25 more authors.
PLoS Genetics | Year: 2013

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al.

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