Biomedical subjects

Thierry Gilbert

Publications and source records attributed to Thierry Gilbert.

7 recordsLinked to original sources

PubMed2004

Expression of retinoic acid-synthesizing and -metabolizing enzymes during nephrogenesis in the rat.

Vitamin A signaling through its active form retinoic acid (RA) plays a critical role during kidney development and vitamin A deficiency in the rat induces renal hypoplasia. Here, we describe the distribution of four enzymes of the RA synthetic pathway (aldehyde dehydrogenases ALDH1A1-3 and ALDH8A1) and two enzymes of the degradative pathway (CYP26A1 and CYP26B1) in the developing rat metanephros. We provide evidence that each enzyme displays a cell-type specific expression pattern that changes considerably in the course of renal organogenesis and nephron differentiation. ALDH1A2 expression was restricted to the cortical stroma cell population, whereas ALDH8A1 transcripts were present in emerging renal vesicles. CYP26A1 and CYP26B1 mRNAs were absent during this time. Following nephron induction, ALDH1A1 remained weakly expressed in the UB ends, but was highly expressed in the UB-connected tubule and in all differentiating tubular segments of the developing nephron. ALDH1A2 was strongly expressed in the visceral layer of the developing glomeruli, as well as in cortical collecting tubules. ALDH1A3 mRNAs were found in the developing papilla and ureter. During postnatal nephrogenesis, ALDH1A3 and ALDH8A1 were co-expressed in the ureteric bud ends. CYP26A1 and CYP26B1 were both expressed from E18.5 onwards in S-shaped bodies, in tubular and glomerular anlagen, respectively. On the last day of nephrogenesis in the rat, CYP26B1 expression extended to UB ends. Our results indicate that tubular and glomerular differentiation of the nephron relies upon precise control of the RA metabolic pathway.

Aldehyde Dehydrogenase↗

PubMed2004

Long-term effects of in utero exposure to cyclosporin A on renal function in the rabbit.

The number of pregnant women who receive cyclosporin A (CsA) after transplantation or for autoimmune disease has increased. CsA and its metabolites can cross the placental barrier and thus interfere with fetal development. It was shown previously that rabbits that were exposed in utero to 10 mg/kg per d CsA from the 14th to the 18th day of gestation presented a 25% nephron reduction. Thus, this study was conducted to assess the long-term systemic and renal effects of a CsA-induced nephron reduction. Twenty-two pregnant New Zealand white rabbits were randomly divided into two groups: Twelve received 10 mg/kg per d CsA from day 14 to day 18 of gestation, and 10 were used as controls. Rabbits that were born to these animals were evaluated at 4, 11, 18, and 35 wk of life. Pups that were exposed antenatally to CsA presented first a permanent nephron deficit; second, glomerular, tubular, and intrarenal hemodynamics dysfunction; third, enlarged kidneys with numerous tubular and glomerular lesions; and, fourth, an endothelin-dependent systemic hypertension that worsened with age. In utero exposure to CsA induced a nephron reduction that led to systemic hypertension and progressive chronic renal insufficiency in adulthood. A long-term clinical survey is mandatory in infants who are born to mothers who were treated with cyclosporin during pregnancy.

Abnormalities, Drug-Induced↗

PubMed2004

In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation.

BACKGROUND: Mutations in NPHS2, encoding podocin, are a prevalent cause of autosomal-recessive steroid-resistant nephrotic syndrome (SRNS). Podocin is a protein associated with the slit diaphragm that interacts with nephrin and CD2-associated protein (CD2AP) within lipid rafts. METHODS: Using renal biopsies of six patients, we analyzed the in vivo consequences of different types of NPHS2 mutations on (1) the podocyte expression and distribution of podocin using in situ hybridization and immunohistology and (2) the distribution of related podocyte proteins and glomerular extracellular matrix components. RESULTS: In two patients with homozygous 855_856delAA or 419delG mutation, absence of podocyte labeling with the antibodies against the C-terminal domain contrasted with the normal expression of the N-terminal domain of the protein along the glomerular basement membrane (GBM). In patients carrying compound heterozygous mutations or variants (R168S/467_468insT, R138Q/V180M, and R291W/R229Q), or single heterozygous 976_977insA, podocin transcription appeared unchanged but the distribution of the protein was modified. Podocin was restricted to the podocyte body in the patient carrying the R168S/467_468insT mutation whereas strong immunolabeling of the podocyte body was associated with discrete labeling along the GBM in the three others. In all cases, podocin defect was associated with changes in the distribution of nephrin, CD2AP, and alpha-actinin: the proteins were mainly detected in the podocyte body, with mild expression along the GBM. There were no detectable changes in the distribution of other podocyte proteins or glomerular extracellular matrix components. CONCLUSION: NPHS2 mutations result in profound alteration of podocin expression and/or distribution. Secondary changes in the distribution of nephrin, CD2AP, and alpha-actinin are additional evidences for the scaffolding role of podocin in the organization of the slit diaphragm.

Actinin↗

PubMed2003

Cyclosporin A administration during pregnancy induces a permanent nephron deficit in young rabbits.

Cyclosporin A (CsA) is an immunosuppressive agent used to prevent graft rejection and to treat autoimmune disorders. Successful pregnancies can be achieved among CsA-treated women, although it is known that CsA is nephrotoxic and crosses the human placenta. The aim of this study was to evaluate the harmlessness of CsA toward the embryonic kidney. Twenty-one pregnant rabbits were divided into four groups. Groups of six and four female animals were subjected to daily injections of 10 mg/kg per d CsA (administered subcutaneously) for 5 d, from day 14 to day 18 of gestation or from day 20 to day 24 of gestation, respectively. In the third group, five female animals received the CsA diluent (Cremophor) from day 14 to day 18 of gestation. The fourth group consisted of six untreated female animals. Pregnancy outcomes among CsA-treated does demonstrated a reduced number of living pups, which were also growth-retarded, with exposure to CsA from day 20 to day 24 of gestation. However, pups exposed to CsA from day 14 to day 18 of gestation exhibited normal fetal growth, and blood concentrations of CsA matched human data. Examinations of kidneys at birth demonstrated vacuolation of proximal and collecting tubules and ureteric bud ends. Increased glomerular volumes and decreased nephron densities suggested nephron mass reduction, which was quantitatively evaluated in 1-mo-old animals. The nephron numbers were reduced by 25 and 33% in day 14 to 18 CsA-treated and day 20 to 24 CsA-treated animals, respectively, which displayed compensatory adaptation of the existing nephrons. However, foci of segmental glomerular sclerosis were already present, which would possibly jeopardize renal function later in life.

Age Factors↗

PubMed2002

Vitamin A and kidney development.

Recent advances in developmental nephrology have provided new evidence that retinoids, vitamin A and its active metabolites such as all-trans retinoic acid, profoundly influence renal organogenesis. Retinoids are acknowledged as potent nephron mass regulators. They regulate embryonic kidney patterning through control of Ret expression in a dose-dependent manner, which modulates ureteric bud branching morphogenesis. Analysis of retinoid availability and utilization provides additional evidence of retinoid involvement at sites of epithelial-mesenchymal interactions, suggesting a tight control of vitamin A homeostasis for proper renal morphogenesis and differentiation. This provides a rationale for the search for and identification of retinoid target genes.

Animals↗

PubMed2000

In utero and in vitro exposure to beta-lactams impair kidney development in the rat.

beta-Lactam antibiotics are widely used because of their lack of toxicity in humans. However, during pregnancy, exposure of the fetus is likely to occur because beta-lactam antibiotics cross the placenta. The potential adverse effects of two penicillins (ampicillin, amoxicillin) and of one cephalosporin (ceftriaxone) were examined in rat kidney development. Two experimental approaches were used: metanephros organ cultures to analyze the direct effect of the drug and maternal treatment to assess the consequences of in utero exposure. For in vitro experiments, metanephroi were removed from 14-d-old fetuses and grown with or without the antibiotic at a concentration ranging from 10 to 1000 microg/ml for 6 d. For in vivo experiments, pregnant rats were treated with penicillin at 100 mg/kg per d for 5 d, a period overlapping early renal organogenesis. Both penicillins alter renal development in vitro in a dose-dependent manner, from a dose of 10 microg/ml for ampicillin and 100 microg/ml for amoxicillin. In young animals exposed to penicillins in utero, a mild oligonephronia was present and cystic tubule dilation was observed in newborn and in young animals as well. Ceftriaxone weakly impairs in vitro nephrogenesis except at the dose of 1000 microg/ml that blocks kidney development completely. No effect on nephron ontogeny was observed following in utero exposure, but an interstitial inflammation was present in the medulla of 2-wk-old rats. In conclusion, these data show that beta-lactams, at therapeutic doses, are harmful to fetal rat kidneys.

Amoxicillin↗

PubMedDate not supplied

Recent advances in Dyggve-Melchior-Clausen syndrome.

Dyggve-Melchior-Clausen (DMC) is a rare autosomal-recessive disorder characterized by the association of a progressive spondylo-epi-metaphyseal dysplasia and mental retardation ranging from mild to severe. Electron microscopy studies of both DMC chondrocytes and fibroblasts reveal an enlarged endoplasmic reticulum network and a large number of intracytoplasmic membranous vesicles, suggesting that DMC syndrome may be a storage disorder. Indeed, DMC phenotype is often compared to that of type IV mucopolysaccharidosis (Morquio disease), a lysosomal disorder due to either N-acetylgalactosamine-6-sulphatase or beta-galactosidase deficiency. To date, however, the lysosomal pathway appears normal in DMC patients and biochemical analyses failed to reveal any enzymatic deficiency or accumulated substrate. Linkage studies using homozygosity mapping have led to the localization of the disease-causing gene on chromosome 18q21.1. The gene was recently identified as a novel transcript (Dym) encoding a 669-amino acid product (Dymeclin) with no known domains or function. Sixteen different Dym mutations have now been described in 21 unrelated families with at least five founder effects in Morocco, Lebanon, and Guam Island. Smith-MacCort syndrome (SMC), a rare variant of DMC syndrome without mental retardation, was shown to be allelic of DMC syndrome and to result from mutations in Dym that would be less deleterious to the brain. The present review focuses on clinical, radiological, and cellular features and evolution of DMC/SMC syndromes and discusses them with regard to identified Dym mutations and possible roles of the Dym gene product.

Abnormalities, Multiple↗