[NGAL: a biomarker of acute and chronic renal dysfunction]. / La lipocaline NGAL : biomarqueur d'altération aiguë et chronique de la fonction rénale.

Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein of 25 kDa belonging to the superfamily of lipocalins, which counts low molecular mass proteins having the capacity to fix the iron. The NGAL presents bacteriostatic properties and is a factor of growth and differentiation, especially in response to renal tissue damage and during the nephrogenesis. Since the past 10 years, numerous clinical studies suggest that urinary and/or blood levels of NGAL could be a relevant biomarker of acute or chronic renal failure, in particular in the context of the diabetic nephropathy. NGAL could be a more sensitive and more specific marker than the albuminuria and might detect the early appearance of the renal lesions, and thus could be useful to prevent or reduce severity of renal function alterations.

The gene encoding fibrinogen-beta is a target for retinoic acid receptor-related orphan receptor alpha.

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (alpha, beta, gamma). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)alpha is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORalpha as a regulator of fibrinogen-beta gene expression in human hepatoma cells and in mouse liver. A putative RORalpha response element (RORE) was identified in the human fibrinogen-beta promoter. EMSA showed that RORalpha binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORalpha-dependent transcriptional activation to both the human fibrinogen-beta and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORalpha specifically increases endogenous fibrinogen-beta mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-beta RORE is occupied by RORalpha in HepG2 cells. Thus, the human fibrinogen-beta gene is a direct target for RORalpha. Furthermore, fibrinogen-beta mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORalpha in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.

Repression of alpha-fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor-1 and c-Myc.

Hypoxia is an important component of many pathological processes including cancerogenesis and cirrhosis. We have attempted to identify additional hepatic genes sensitive to hypoxia by postulating that genes with possible binding sites for hypoxia inducible factor-1 (HIF-1) are regulated by hypoxia. A computer analysis identified the oncodevelopmental alpha-fetoprotein gene (afp) as one of them. The amounts of both alpha-fetoprotein mRNA and protein were decreased under hypoxic conditions in HepG2 hepatoma cells. Stability of afp mRNA was not altered, and de novo synthesis of proteins was required. Transfection experiments in HepG2 cells showed that both hypoxia and overproduction of HIF-1alpha specifically repressed the transcriptional activity of the rat afp regulatory region through the sequence 5'-CACGTGGG-3' located at -3625 to -3619. Mutation in this sequence strongly impaired these repressions. Interestingly, this sequence was a functional stimulatory target for c-Myc, suggesting that c-Myc regulates afp gene expression. Lastly, the amounts of c-myc mRNA and protein were reduced when these cells were grown under hypoxic conditions. Taken together, these results suggest the existence of a possible competition between HIF-1 and c-Myc that could modulate the transcriptional activity of the afp gene in response to hypoxia.

Medically assisted reproduction and second-trimester maternal serum marker screening for Down syndrome.

OBJECTIVES: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on total hCG, free ss-hCG, AFP and unconjugated estriol (uE3) used as markers for second-trimester Down syndrome maternal serum screening. METHODS: Second-trimester maternal sera from 1515 singleton pregnancies (970 by IVF, 545 by ICSI) were compared with control sera (21 014 cases). Free ss-hCG, total hCG, AFP and uE3 were compared between the control group and the medically assisted reproduction groups. The percentages of at-risk patients (>/=1/250) were also compared. RESULTS: No differences in values of the maternal serum markers were observed between the medically assisted and control groups. When maternal age was taken into account, the screen-positive rate for Down syndrome screening did not differ between the two groups. CONCLUSION: Patients undergoing assisted reproduction techniques can be counseled for maternal serum Down syndrome screening with the same efficacy as patients with naturally conceived pregnancies.