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In the fully developed kidney, gamma-glutamyltranspeptidase is localized predominantly to the apical plasma membrane of the proximal tubules. The appearance of this activity during murine fetal nephrogenesis was quantitated using a sensitive fluorometric assay, and development of membrane polarity was assessed by immunocytochemistry. Specific activity of the transpeptidase in 13-day fetal kidney was approximately 1 mU/mg protein. Between 13-21 days of gestation, total transpeptidase activity increased 7500-fold, whereas specific activity increased 50-fold. At 13 days of gestation, gamma-glutamyltranspeptidase immunoreactivity is localized to the apical surfaces of developing renal vesicles and the proximal segment of the S-shaped tubules. The organized cell structures have tight tubular junctions but lack a well-defined brush-border membrane. By 15 days of gestation, immunostaining of the apical surface of developing proximal segments is more prominent, and slight reactivity of the basolateral membrane is evident. By 17 days of gestation, the kidney is organized into discrete zones. The large increase in gamma-glutamyltranspeptidase activity correlates with the appearance of increased immunostaining of the developing brush-border membranes of the proximal tubules contained in the inner cortex. A very similar although somewhat delayed pattern of appearance of transpeptidase activity and immunostaining was observed in metanephric organ culture. Induction of proximal tubular cyst formation had no effect on the increase in transpeptidase activity that occurred during organotypic nephrogenesis.  相似文献   

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MUC1 is a transmembrane glycoprotein, apically expressed in most epithelial cells, used in the differential diagnosis of carcinomas and for discrimination of tumors of non-epithelial origin showing epithelioid features. Little attention has been paid so far though, on its possible significance in embryonic tissues. A preliminary study from our group revealed MUC1 expression in the cap mesenchymal cells during human nephrogenesis, suggesting a role for MUC1 in the process of mesenchymal-to-epithelial transition. This study aimed at investigating the expression pattern of MUC1 in various developing structures of human fetal kidney. Expression of MUC1 was examined in kidneys of 5 human fetuses. MUC1 immunoreactivity was detected in ureteric bud tips, in collecting tubules, in cap mesenchymal cells undergoing the initial phases of mesenchymal-to-epithelial transition, in renal vesicles, comma-bodies, and S-shaped bodies. Our previous preliminary report suggested a role for MUC1 in the initial phases of the process of mesenchymal-to-epithelial transition. The present data suggest that MUC1 expression characterizes multiple structures during human nephrogenesis, from the ureteric bud, to the initial phases of mesenchymal-to-epithelial transition and that MUC1 should be added to the genes activated during the process of mesenchymal-to-epithelial transition in the cap mesenchyme of human kidney.Key words: MUC1, immunohistochemistry, fetal kdney, nephrogenesis, renal vesicles, comma and S-shaped bodies, collecting tubules.  相似文献   

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Exposure to hyperglycemia in utero impairs rat nephrogenesis. The effect of maternal diabetes on insulin-like growth factors and their receptors in the fetal kidney is associated with an increase in both mRNA and protein of the insulin-like growth factor II/mannose 6-phosphate receptor. However, this receptor has never been localized in the fetal kidney. The spatial and temporal distribution of the three insulin-like growth factor receptors (insulin-like growth factor I receptor, insulin-like growth factor II/mannose 6-phosphate receptor and insulin receptor) in rat metanephros during both normal and streptozotocin-induced diabetic renal development was investigated using in situ hybridization and immunohistochemistry. All receptors were found in the fetal kidney from the start of nephrogenesis. Insulin-like growth factor I receptor expression was ubiquitous and continuously present during metanephric development. Insulin receptor expression was developmentally regulated during kidney maturation with an enhanced expression in proximal tubules at the late stages of development. Insulin-like growth factor II/mannose 6-phosphate receptor expression was ubiquitous in the early stages of development and was dramatically decreased at the late stages of normal kidney development. Insulin receptor and insulin-like growth factor I receptor expressions were unchanged in diabetic metanephroi. Although the spatial expression of insulin-like growth factor II/mannose 6-phosphate receptor was unaffected by hyperglycemia, its expression was not downregulated in the mesenchyme of the nephrogenic zone of diabetic fetuses on gestational day 20. This study suggests a crucial role of insulin-like growth factor II/mannose 6-phosphate receptor in the pathogenesis of the impaired nephrogenesis in fetuses of diabetic mothers.  相似文献   

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This study describes cDNA cloning and characterization of mouse RALDH4. The 2.3-kb cDNA encodes an aldehyde dehydrogenase of 487 amino acid residues, about two-orders of magnitude more active in vitro with 9-cis-retinal than with all-trans-retinal. RALDH4 recognizes as substrate 9-cis-retinal generated in transfected cells by the short-chain dehydrogenases CRAD1, CRAD3, or RDH1, to reconstitute a path of 9-cis-retinoic acid biosynthesis in situ. Northern blot analysis showed expression of RALDH4 mRNA in adult mouse liver and kidney. In situ hybridization revealed expression of RALDH4 in liver on embryo day 14.5, in adult hepatocytes, and kidney cortex. Immunohistochemistry confirmed RALDH4 expression in hepatocytes and showed that hepatocytes also express RALDH1, RALDH2, and RALDH3. Kidney expresses the RALDH4 protein primarily in the proximal and distal convoluted tubules of the cortex but not in the glomeruli or the medulla. Kidney expresses RALDH2 in the proximal convoluted tubules of the cortex but not in the distal convoluted tubules or glomeruli. Kidney expresses RALDH1 and RALDH2 in the medulla. The enzymatic characteristics of RALDH4, its expression in fetal liver, and its unique expression pattern in adult kidney compared with RALDH1, -2, and -3 suggest that it could meet specific needs for 9-cis-retinoic acid biosynthesis.  相似文献   

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Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary disease affecting the kidneys, is caused in 85% of cases by mutations in the PKD1 gene. The protein encoded by this gene, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment, which regulate the tissue architecture and differentiation. However, how such mutations result in the formation of cysts is still unclear. We performed a precise characterization of mesenchymal differentiation using PAX2, WNT4 and WT1 as a marker, which revealed that impairment of the differentiation process preceded the development of cysts in Pkd1(-/-) mice. We performed an in vitro organ culture and found that progesterone and a derivative thereof facilitated mesenchymal differentiation, and partially prevented the formation of cysts in Pkd1(-/-) kidneys. An injection of progesterone or this derivative into the intraperitoneal space of pregnant females also improved the survival of Pkd1(-/-) embryos. Our findings suggest that compounds which enhance mesenchymal differentiation in the nephrogenesis might be useful for the therapeutic approach to prevent the formation of cysts in ADPKD patients.  相似文献   

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Kidney androgen-regulated protein (KAP) mRNA represents the most abundant [approximately 4% of the total poly(A) RNA] mRNA species that is induced by androgens in the mouse kidney. Comparison of the expression of several androgen-regulated mRNAs in this tissue, revealed that the mRNAs were differentially regulated by the hormone. KAP mRNA exhibited unusual sensitivity to low concentrations of the androgen-receptor complex. Because of its unusual characteristics, it was of interest to determine in what cells of the kidney KAP mRNA was being produced. Using the technique of in situ hybridization with single stranded RNA probes, we have identified the epithelial cells of the renal proximal convoluted tubules as the site of synthesis of KAP mRNA. Interestingly, only a subpopulation of these cells, those located in the juxtamedullary region of the renal cortex, contain KAP mRNA in castrated males. After androgen treatment, cortical proximal tubules are also induced to express KAP mRNA. These results suggest that two types of response to androgens occur in these cells. One is the progressive increase of KAP gene expression in the juxtamedullary region while the other involves recruitment of new cells in the cortical proximal tubules to synthesize KAP mRNA.  相似文献   

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PAX8-mediated activation of the wt1 tumor suppressor gene.   总被引:3,自引:0,他引:3       下载免费PDF全文
M Dehbi  J Pelletier 《The EMBO journal》1996,15(16):4297-4306
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Expression of the PAX2 gene in human fetal kidney and Wilms' tumor.   总被引:8,自引:0,他引:8  
We have examined the pattern of expression of the human PAX2 gene in Wilms' tumors and human fetal kidney by Northern blot and in situ hybridization. Human PAX2 encodes a paired box-containing protein and has a high degree of homology with mouse and Drosophila paired box genes. In situ hybridization analysis reveals that PAX2 is expressed in nephrogenic structures in fetal kidney and also in Wilms' tumors. This pattern of expression suggests that PAX2 may have a role in differentiation of tissues in the kidney. In fetal kidney, PAX2 expression rapidly attenuates following the initial differentiation, but no evidence of attenuation was found in Wilms' tumors. The timing of PAX2 expression is restricted to fetal development, although high levels of expression were also observed in nephrogenic rests of residual normal juvenile kidney tissue adjacent to a Wilms' tumor. Nephrogenic rests are the presumptive precursors of Wilms' tumor but are not necessarily neoplastic. The failure of PAX2 expression to attenuate in Wilms' tumors and nephrogenic rests may be associated with events leading to the onset of Wilms' tumor. By somatic cell hybrid mapping, the PAX2 gene was localized to chromosome 10q22.1-q24.3, although this region has not previously been implicated in Wilms' tumor.  相似文献   

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Formation of kidney tissue requires the generation of kidney precursor cells and their subsequent differentiation into nephrons, the functional filtration unit of the kidney. Here we report that the gene odd-skipped related 1 (Odd1) plays an important role in both these processes. Odd1 is the earliest known marker of the intermediate mesoderm, the precursor to all kidney tissue. It is localized to mesenchymal precursors within the mesonephric and metanephric kidney and is subsequently downregulated upon tubule differentiation. Mice lacking Odd1 do not form metanephric mesenchyme, and do not express several other factors required for metanephric kidney formation, including Eya1, Six2, Pax2, Sall1 and Gdnf. In transient ectopic expression experiments in the chick embryo, Odd1 can promote expression of the mesonephric precursor markers Pax2 and Lim1. Finally, persistent expression of Odd1 in chick mesonephric precursor cells inhibits differentiation of these precursors into kidney tubules. These data indicate that Odd1 plays an important role in establishing kidney precursor cells, and in regulating their differentiation into kidney tubular tissue.  相似文献   

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R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/β-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/β-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/β-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/β-catenin signaling pathway.  相似文献   

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