Calcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients.
BMP-7, a member of the bone morphogenic protein subfamily (BMPs) of the transforming growth factor-β superfamily of secreted growth factors, is abundantly expressed in the fetal kidney. The precise role of this protein in renal physiology or pathology is unknown. A cDNA that encodes rat BMP-7 was cloned and used as a probe to localize BMP-7 mRNA expression by in situ hybridization in the adult rat kidney. The highest expression of BMP-7 mRNA could be seen in tubules of the outer medulla. In glomeruli, a few cells, mainly located at the periphery of the glomerular tuft, showed specific and strong signals. Also, high BMP-7 mRNA expression could be localized to the adventitia of renal arteries, as well as to the epithelial cell layer of the renal pelvis and the ureter. Preliminary evidence suggests that BMP-7 enhances recovery when infused into rats with ischemia-induced acute renal failure. We examined BMP-7 mRNA expression in kidneys with acute renal failure induced by unilateral renal artery clamping. BMP-7 mRNA abundance as analyzed by solution hybridization was reduced in ischemic kidneys after 6 and 16 h of reperfusion compared with the contralateral kidney. In situ hybridization in ischemic kidneys showed a marked decrease of BMP-7 mRNA in the outer medulla and in glomeruli. Utilizing rat metanephric mesenchymal cells in culture, we also demonstrate that BMP-7 induces epithelial cell differentiation. Taken together, these data suggest that BMP-7 is important in both stimulating and maintaining a healthy differentiated epithelial cell phenotype.
Bone morphogenetic proteins (BMPs) play an important role in nephrogenesis. The biologic effect and mechanism of action of these proteins in the adult kidney has not yet been studied. We investigated the effect of BMP2, a member of these growth and differentiation factors, on mitogenic signal transduction pathways induced by platelet-derived growth factor (PDGF) in glomerular mesangial cells. PDGF is a growth and survival factor for these cells in vitro and in vivo. Incubation of mesangial cells with increasing concentrations of BMP2 inhibited PDGF-induced DNA synthesis in a dose-dependent manner with maximum inhibition at 250 ng/ml. Immune complex tyrosine kinase assay of PDGF receptor  immunoprecipitates from lysates of mesangial cells treated with PDGF showed no inhibitory effect of BMP2 on PDGF receptor tyrosine phosphorylation. This indicates that the inhibition of DNA synthesis is likely due to postreceptor events. However, BMP2 significantly inhibited PDGF-stimulated mitogen-activated protein kinase (MAPK) activity that phosphorylates the Elk-1 transcription factor, a component of the ternary complex factor. Using a fusion protein-based reporter assay, we also show that BMP2 blocks PDGF-induced Elk-1-mediated transcription. Furthermore, we demonstrate that BMP2 inhibits PDGF-induced transcription of c-fos gene, a natural target of Elk-1 that normally forms a ternary complex that activates the serum response element of the c-fos gene. These data provide the first evidence that in mesangial cells, BMP2 signaling crosstalks with MAPK-based transcriptional events to inhibit PDGF-induced DNA synthesis. One target for this inhibition is the early response gene c-fos.Bone morphogenetic proteins are a group of growth and differentiation factors that were originally identified by their ability to form ectopic bone (1, 2). Recently several members of this family have been cloned. These proteins contain seven highly conserved cysteines in the C terminus that are characteristic of the TGF- 1 family of proteins and thus fall into that broad superfamily (3-6). BMPs play an important role in the development of many organs, including lung, heart, teeth, gut, skin, and particularly the kidney (4). BMP7, a member of this large family, has been shown to be abundantly expressed in the ureteric bud epithelium before condensation of mesenchyme during nephrogenesis. BMP7 is also expressed during glomerulogenesis (7). BMP7 null mice die after birth because of early cessation of kidney development (8, 9). The rudimentary kidneys at birth lack glomeruli, the filtering units, likely due to lack of differentiation of metanephric mesenchymal cells (8).High affinity binding of BMP2, another member of this family, has been identified in a large variety of tissues and cells, including the kidney (10). Similar to TGF-, BMPs exert their effect via type I and type II transmembrane serine-threonine kinase receptors (4 -6). Binding of BMPs to the receptor induces phosphorylation of the type I receptor in the intracellular GS domain (6). S...
The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus-thymidine kinase (HSV-tk)-mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.
Summa,-r W'e examined levels of mRNA and protein for N-cadhein. the predominant cadhenrn in neural tissues, and mRNNA levels for the cadherin-associated protein. x-catenin. in a senes of gliomas and in glioblastoma cell lines. mRNA levels for N-cadhenrn and c-catenin were significantly higher in glioblastomas than in low-erade astrocvtomas or normal brain. while the levels of intact N-cadherin protein were similar in glioblastomas. low-grade astrocvtomas and brain. In addition. there A-as no consistent relationship betv-een invasiveness and expression of N-cadhenin and ci-catenin in highly invasive vs minimally invasive tumours A-ithin the same histopathological grade. To assess further the relationship between cadherin expression and neural tumour invasion, we measured N-cadherin expression. calcium-dependent cell adhesion and motility of several glioblastoma cell lines. While all N-cadhenrn-expressing lines u-ere adhesive, no correlation was seen between the level of N-cadherin expression and cell motility; Together. these findings imply that, in contrast to the role played by E-cadhenrn in carcinomas. N-cadherin does not restnrct the invasion of glioblastomas.
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