Christelle Cauffiez

Université de Lille · Faculty of Medicine

Abstract Non-small cell lung cancer is characterized by a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Therefore, the identification of new molecular determinants underlying sensitivity of cancer cells to existing therapy is of particular importance to develop new effective combinatorial treatment strategy....

Introduction and main objectives Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible interstitial lung disease (ILD), that increases dramatically in incidence and prevalence with age. While successful alveolar regeneration after injury depends on pulmonary capillary endothelial cells (PCEC) reprogramming, the steps involv...

Variability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding prote...

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that li...

MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chr...

Introduction L’hypophosphatémie est fréquente (60 %) au cours des hépatites aiguës (HA). Nous démontrons ici qu’elle est secondaire à un diabète phosphaté (DP) et son lien avec le FGF23. Description Nous avons constaté l’existence d’un DP associé à un taux élevé de FGF23 chez des patients atteints d’HA. Leurs biopsies hépatiques ont étés analysées...

Thousands of unique noncoding RNAs (ncRNAs) are expressed in human cells, some are tissue or cell type specific whereas others are considered as house‐keeping molecules. Studies over the last decade have modified our perception of ncRNAs from transcriptional noise to functional regulatory transcripts that influence a variety of molecular processes...

Simple Summary Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional systemic therapies and also known for abnormal lipid accumulation. Identifying the actors and deciphering the molecular mechanisms that lead to tumor progression is an important step in the development o...

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant...

Sepsis is the leading cause of acute kidney injury (AKI) in critical care patients. A cornerstone of sepsis-associated AKI is dysregulated inflammation driven by excessive activation of Toll-like receptor 4 (TLR4) pathway. MUC1, a membrane bound mucin expressed in both epithelial tubular cells and renal macrophages, has been shown to be involved in...

Résumé Le processus de cancérogenèse est traditionnellement considéré comme un processus multi-étapes ayant pour origine l’activation d’oncogènes et l’inactivation de gènes suppresseurs de tumeur. Néanmoins, les mécanismes qui sous-tendent la tumorigenèse ne se résument pas aux seules altérations moléculaires et nécessitent d’être appréhendés dans...

Introduction Bien que leur efficacité soit démontrée en oncologie, le recours aux sels de platine reste limité par le risque de survenue d’une insuffisance rénale aiguë (IRA). Un rôle potentiel de la caféine dans cette physiopathologie a été suggéré, notamment par le biais de ses effets hémodynamiques. Description Il s’agit d’une étude monocentriq...

Next-generation sequencing has revolutionized the molecular diagnosis of individuals affected by genetic kidney diseases. Indeed, rapid genetic testing in individuals with suspected inherited nephropathy has not only important implications for diagnosis and prognosis but also for genetic counseling. Nephronophthisis (NPHP) and related syndromes, a...

Cadmium is an environmental pollutant well known for its nephrotoxic effects. Nevertheless, mechanisms underlying nephrotoxicity continue to be elucidated. MicroRNAs (miRNAs) have emerged in recent years as modulators of xenobiotic-induced toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in renal proximal tubula...

Abstract Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated...

Purpose Cisplatin-induced acute kidney injury (CIA) is a serious adverse event that affects 20–40% of exposed patients, despite any implemented precaution to avoid it. The aim of this work was therefore to identify a relevant nephroprotective method for CIA. Methods We searched Pubmed, Embase, and Web of Science from 1 January 1978 to 1 June 2018,...

Purpose Cisplatin-induced acute kidney injury (CIA) is a serious adverse event that affects 20–40% of exposed patients, despite any implemented precaution to avoid it. The aim of this work was therefore to identify a relevant nephroprotective method for CIA. Methods We searched Pubmed, Embase, and Web of Science from 1 January 1978 to 1 June 2018,...

Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic opti...

Rationale: Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. TGF-β (transforming growth factor-β) is the main profibrotic factor,...

Pro‐aging effects of endogenous advanced glycation end‐products (AGEs) have been reported, and there is increasing interest in the pro‐inflammatory and ‐fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill‐defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CM...

Background: Tacrolimus exhibits pharmacokinetics variability partly explained by CYP3A5 activity. In contrast to *3/*3 genotype, those carrying at least one CYP3A5*1 allele exhibit higher enzyme activity leading to lower Tac trough blood level despite higher daily dose. In this study, we aimed to evaluate the impact of CYP3A5 polymorphism on renal...

Introduction Les lésions de fibrose rénales représentent une caractéristique commune des maladies rénales chroniques et participent, à terme, au développement d’insuffisance rénale chronique terminale. Bien que miR-21 soit un microARN communément impliqué dans le processus de fibrose rénale, les données expérimentales de la littérature restent cont...

Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrol...

Given the paucity of effective treatments for fibrotic disorders, new insights into the deleterious mechanisms controlling fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Here, we identified the long non-coding RNA DNM3OS as a critical downstream effector of TGF-β-induced...

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a we...

Acute kidney injury (AKI) is characterized by acute tubular necrosis (ATN) which involves mainly proximal tubules. Past AKI is associated with higher risk of chronic kidney disease (CKD). The MUC1 mucin is a large glycoprotein responsible for epithelial protection and locates to convoluted distal tubules and collecting ducts. Since MUC1 activates t...

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, whose prognosis is highly variable. Interstitial fibrosis is a strong independent prognosis factor. Among microRNA involved in renal fibrogenesis, only few have been investigated in IgAN. In the context of IgAN, we aimed to analyze the role of miR-21-5p, miR-214-3p and miR-199...

Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function with accumulation of extracellular matrix components in the renal parenchyma. The molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the p...

Background Identification of the culprit genes underlying multifactorial diseases is one of the most important current challenges of molecular genetics. While recent advances in genomics research have accelerated the discovery of susceptibility genes, much remains to be learned about the functions of disease-associated genetic variants. Recently, M...

The contribution of epithelial-mesenchymal transition (EMT) has been suggested in renal transplant recipients receiving calcineurin inhibitors and developing nephrotoxicity. We assessed whether interindividual variability in tacrolimus pharmacokinetics is associated with the occurrence in tubular cells of two EMT markers (vimentin, β-catenin) detec...

Introduction Lors de l’évolution de la maladie de Berger, les lésions de fibrose interstitielle (FI) sont déterminantes pour le pronostic rénal. Les microARN (miR) sont de petits ARN non codants impliqués dans la régulation post-transcriptionnelle. In vitro, et dans des modèles murins de FI, miR-21 et miR-199a-5p ont été décrits comme pro-fibrosant...

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that...

Introduction and Aims: IgA nephropathy (IgAN) encompasses different pathological entities all which are characterized by the mesangial deposition of IgA. Sclerotic lesions in IgAN mainly form as a consequence of healing of inflammatory lesions. Mesangial cells serve as primary glomerulat type injury, but recent evidence suggests that podocyte injur...

Fibrosis, or tissue scarring, is defined as excessive and persistent accumulation of extracellular matrix components in response to chronic tissue injury. Fibrosis is a pathological feature characterizing nearly all forms of chronic organ failure. Fibroproliferative disorders of liver, kidney, heart, and lung are frequently associated with consider...

MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carc...

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 tubu...

Phenotypic analysis of commercial PT cells. Fluorescence plot showing commercial PT cells (from ScienCell Research Laboratories, Nanterre, France) labeled with antibodies against CD10 (APC: allophycocyanin) and CD13 (PE: phycoerythrin) after three passages. Flow cytometry revealed about 42% double-positive cells. (TIF)

Summary of forward and reverse primers used to generate PCR products. (DOC)

Expression of α-SMA in different cell populations. (A) Representative immunoblotting of (1) unsorted cells, (2) CD10+ cells, (3) CD13+ cells, (4) CD10/CD13 double-negative cells, (5) PT cells at passage 2, (6) PT cells at passage 3, (7) PT cells at passage 4 and (8) PT cells at passage 5. Blots were incubated with antibody against α-SMA. The β-acti...

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 m...

Study schema. (TIF)

miR-199a-5p and pri-miR-199a expression in C57BL/6 mice 14 days following bleomycin exposure. (A) Real-time PCR was performed to confirm the enhanced expression of miR-199a-5p in lungs of C57BL/6 and BALB/C mice 14 days following bleomycin exposure on an independent set of mice (n = 5 mice in each group). Data are expressed as mean ± SEM. *p<0.05....

CAV1 is a direct target of miR-199a-5p. Co-transfection of pre-miR-199a-5p or pre-miR-Neg and human CAV1 3′UTR-derived psiCHECK-2 construct in A549 cells show a significant decrease in normalized luciferase activity 48 h post-transfection. * p<0.05. (TIF)

Decreased CAV1 expression after transfection of MRC5 lung fibroblasts with pre-miR-199a-5p. (A) MRC5 Lung fibroblasts that were transfected with 10 nM of pre-miR-199a-5p for 48 h show a significant decrease in CAV1 expression as determined by real-time PCR. Data are expressed as mean ± SEM. **p<0.01. (B) Western blot analysis showing the downregula...

MiR-199a-5p expression determined by qPCR using FFPE lung samples. Box plot showing the increased expression of miR-199a-5p in IPF samples (n = 10) compared to control (n = 10). Significance was evaluated using the Kruskal–Wallis rank-sum test. The box represents the 25–75% quartiles, the line in the box represents the median and whiskers represent...

Comparison of gene expression changes between miR-199a-5p-regulated genes in hFL1 human lungs fibroblasts and lungs from C57BL/6 mice 14 days after bleomycin injection. (A) Venn diagram showing the relationships of gene expression changes between miR-199a-5p transfected lung fibroblasts (two independent experiments) and lungs from C57BL/6 14 days a...

miR-21 expression during bleomycin induced lung fibrosis. (A) Normalized fluorescence expression values of miR-21 in lungs from Balb/c and C57BL/6 mice in response to bleomycin at the indicated time points from microarrays experiments (n = 3). Data are expressed as mean ± SEM. **p<0.01 (B) Real-time PCR was performed to confirm the enhanced express...

MiR-199a-5p mediates TGFβ dependent differentiation of lung fibroblast into myofibroblasts through CAV1 regulation. Normal human pulmonary fibroblasts MRC5 were transfected with a control LNA inhibitor (LNA-CT), a LNA-miR-199a-5p inhibitor or a target site blocker directed against CAV1 3-UTR (CAV1 protector) (n = 2). Protein samples were harvested...

Pulmonary expression of CAV1 in BALB/c mice 14 days after bleomycin injection. Real-time PCR was performed to assess the expression of CAV1 in lungs of BALB/c mice 14 days following bleomycin exposure. n = 5 mice in each group, data are expressed as mean ± SEM. n.s. = non significant. (TIF)

Profibrotic genes significantly modulated in lung fibroblasts by miR-199a-5p independently of CAV1 regulation. Lung fibroblasts were transfected by miR-199a-5p mimic, si-CAV1 or negative controls. Microarray analysis shows the expression of known profibrotic genes: TGFBRI (A), MMP3 (B), CAV2 (C), PLAU (D) and CCL2 (E) 48 h after transfection. Data...

List of themes corresponding to “canonical pathways” annotations identified by Ingenuity Pathway Analysis in response to overexpression of miR-199a-5p or miR-21 in human pulmonary fibroblasts hFL1. Normal human pulmonary fibroblasts hFL1 were transfected with pre-miR-Neg, pre-miR-199a-5p or pre-miR-21 (n = 2). RNA samples were harvested at 48 h pos...

List of the 133 genes modulated by miR-199a-5p in lung fibroblasts that are also dysregulated in lungs from C57BL/6 mice 14 days after bleomycin treatment. (DOCX)

Expression of ACTA2 and PPARG following overexpression of miR-199a-5p in lung fibroblasts. Microarray analysis of lung fibroblasts transfected with 10 nM of miR-199a-5p mimic or miR-Neg reveals a significant increase of ACTA2 expression (*p<0.05), a hallmark of myofibroblast differentiation, as well as a significant decrease of PPARG expression (**...

Transfection of human lung fibroblasts with pre-miR-199a-5p or pre-miR-21 increases cell motility. Sratch wound was induced in confluent cell monolayers plated on plastic and wound closure was measured using image J software (2 independent experiments). (TIF)

Effect of TGFβ on mature and pri-miRNAs forms of miR-199a in human lung fibroblasts. HFL1 human fibroblasts were treated or not with 10 nM TGFβ for 48 hours. Real Time TaqMan PCR showing the levels of (A) mature miR-199a-5p and miR-199a-3p; (B) pri-miR-199a-1 and pri-miR-199a-2. n = 2. Data are expressed as mean ± SEM *p<0.05. (TIF)

Comparison of transcriptomic changes induced by miR-199a-5p and a siRNA directed against CAV1. Normal human pulmonary fibroblasts hFL1 were transfected with pre-miR-Neg, pre-miR-199a-5p as well as siCAV1 or a control siRNA (n = 2). RNA samples were harvested at 48 h post-transfection and expression profiles were determined with pan genomic arrays....

Enhanced expression of miR-199a-5p in clinical samples from patients with liver fibrosis. In situ hybridization assay was performed to determine the localization of miR-199a-5p in normal and fibrotic human livers. Results represent one out of three independent experiments. (TIF)

Expression of miR-199a-3p in lung fibrosis and impact of its overexpression on pulmonary fibroblast differentiation. (A) Increased expression of miR-199a-3p and miR-199a-5p in lung samples from IPF patients (n = 10) compared to control lung (n = 10). The mean normalized fluorescence intensity for the agilent probe is displayed; (B) Western blot ana...

List of themes corresponding to “canonical pathways” annotations identified by Ingenuity Pathway Analysis in lungs from C57BL/6 mice treated with bleomycin. RNAs extracted from C57BL/6 mice lungs 14 days after instillation with bleomycin or PBS were analyzed with whole genome microarrays (n = 5).The probability to obtain the number of genes in a ce...

Pulmonary expression of miR-199a-5p in 10 IPF and 10 controls (dataset GEO accession number GSE13316). (DOCX)

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, ne...

The CYP4A subfamily is known to ω-hydroxylate the endogenous arachidonic acid into 20-hydroxyeicosatetranoic acid, which has renovascular and tubular functions. The aim of this work was to report a comprehensive investigation of the CYP4A11 and CYP4A22 genetic polymorphisms in a French population. Using PCR-SSCP and sequencing strategies, a total o...

Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®). This was a prospective, singl...