Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bone morphogenetic proteins, BMP-2 and OP-1, are candidates for growth factors that control renal branching morphogenesis. We examined their effects in embryonic kidney explants and in the mIMCD-3 cell model of collecting duct morphogenesis (mIMCD-3 cells are derived from the terminal inner medullary collecting duct of the SV40 mouse). Osteogenic protein-1 (OP-1), at a dose of 0.25 nM, increased explant growth by 30% (P = 0.001). In contrast, 100-fold greater concentrations of OP-1 (28 nM) decreased explant growth by 10% (P < 0.001). BMP-2 was entirely inhibitory (maximum inhibition of 7% at 5 nM, P < 0.0004). In an in vitro model for branching morphogenesis utilizing the kidney epithelial cell line, mIMCD-3, low doses of OP-1 (< 0.5 nM) increased the number of tubular structures formed by 28 +/- 5% (P = 0.01), whereas concentrations > 0.5 nM decreased that number by 22 +/- 8% (P = 0.02). All concentrations of BMP-2 (0.05-10 nM) were inhibitory (maximum inhibition at 10 nM of 88 +/- 3%, P < 0.0001). Stimulatory doses of OP-1 increased tubular length (P = 0.003) and the number of branch points/structure (3.2-fold increase, P = 0.0005) compared with BMP-2. To determine the molecular basis for these effects, we demonstrated that BMP-2 is bound to mIMCD-3 cells by the type I serine/threonine kinase receptor, ALK-3, and that OP-1 bound to an approximately 80-kDa protein using ligand-receptor affinity assays. To demonstrate that OP-1 can exert both stimulatory and inhibitory effects within a developing kidney, embryonic explants were treated with agarose beads saturated with 2 microM OP-1. OP-1 decreased the number of ureteric bud/collecting duct branches adjacent to the beads by 58 +/- 1% (P < 0.0001). In contrast, the number of branches in tissue distal to the OP-1 beads was enhanced, suggesting a stimulatory effect at lower doses of OP-1. We conclude that OP-1 and BMP-2 directly control branching morphogenesis and that the effects of OP-1 are dependent on its local concentration within developing kidney tissue.
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PMID:BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis. 943 86

Bone morphogenetic protein (BMP)-2 and hepatocyte growth factor (HGF) exert antagonistic effects on renal collecting duct formation during embryogenesis. A current model proposes HGF inhibits BMP-2 signaling at the level of Smad1 in a common target cell. Here, we show that BMP-2 and HGF control collecting duct formation via parallel pathways. We examined the interactions between BMP-2 and HGF in the mIMCD-3 model of collecting duct morphogenesis. During tubule formation, HGF rescued the inhibitory effects of BMP-2 and of a constitutive active form of the BMP-2 receptor, ALK3, stably expressed in mIMCD-3 cells. To determine whether the effect of HGF occurs through known mediators which act downstream of the BMP-2/ALK3 complex, we examined the effect of HGF on BMP-2-induced Smad1 phosphorylation, Smad1/Smad4 complex formation, and Smad1 nuclear translocation. Neither HGF nor other receptor tyrosine kinase ligands (EGF, FGF-4) induced phosphorylation of endogenous Smad1 in mIMCD-3 cells or in Mv1Lu, MC3T3-E1 or P19 cells. Furthermore, none of these ligands blocked induction of the BMP-responsive promoter, Tlx2. Thus, HGF overcomes the inhibitory effects of BMP-2 on collecting duct morphogenesis without interrupting any of the known signaling events in the BMP-2 dependent Smad1 signaling pathway. We conclude that BMP-2/ALK3 and HGF function to control parallel pathways downstream of their respective cell surface receptors. Integration of these signals likely occurs at the level of transcriptional or post-transcriptional events.
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PMID:BMP-2/ALK3 and HGF signal in parallel to regulate renal collecting duct morphogenesis. 1063 78

Renal dysplasia, the most frequent cause of childhood renal failure in humans, arises from perturbations in a complex series of morphogenetic events during embryonic renal development. The molecular pathogenesis of renal dysplasia is largely undefined. While investigating the role of a BMP-dependent pathway that inhibits branching morphogenesis in vitro, we generated a novel model of renal dysplasia in a transgenic (Tg) model of ALK3 receptor signaling. We report the renal phenotype, and our discovery of molecular interactions between effectors in the BMP and WNT signaling pathways in dysplastic kidney tissue. Expression of the constitutively active ALK3 receptor ALK3(QD), in two independent transgenic lines caused renal aplasia/severe dysgenesis in 1.5% and 8.4% of hemizygous and homozygous Tg mice, respectively, and renal medullary cystic dysplasia in 49% and 74% of hemizygous and homozygous Tg mice, respectively. The dysplastic phenotype, which included a decreased number of medullary collecting ducts, increased medullary mesenchyme, collecting duct cysts and decreased cortical thickness, was apparent by E18.5. We investigated the pathogenesis of dysplasia in these mice, and demonstrated a 30% decrease in branching morphogenesis at E13.5 before the appearance of histopathogical features of dysplasia, and the formation of beta-catenin/SMAD1/SMAD4 molecular complexes in dysplastic renal tissue. Increased transcriptional activity of a beta-catenin reporter gene in ALK3(QD);Tcf-gal mice demonstrated functional cooperativity between the ALK3 and beta-catenin-dependent signaling pathways in kidney tissue. Together with our results in the dysplastic mouse kidney, our findings that phospho-SMAD1 and beta-catenin are overexpressed in human fetal dysplastic renal tissue suggest that dysregulation of these signaling effectors is pathogenic in human renal dysplasia. Our work provides novel insights into the role that crucial developmental signaling pathways may play during the genesis of malformed renal tissue elements.
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PMID:Elevated SMAD1/beta-catenin molecular complexes and renal medullary cystic dysplasia in ALK3 transgenic mice. 1273 18

The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.
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PMID:BMP receptor ALK3 controls collecting system development. 1817 1

Bone morphogenetic protein 7 (BMP7) is a key determinant of renal response to injury, exhibiting strong protective as well as regenerative potential in a variety of experimental models. In vitro, beneficial effects of stimulation with BMP7 and other BMPs have been observed in many renal cell types. Still, it remains poorly understood which cells in the native kidney actually respond to BMPs in health and disease. Here, we report the use of BRE:gfp mice expressing green fluorescent protein (GFP) under the control of a pSmad1/5/8-specific BMP-responsive element (BRE) to directly visualize the spatiotemporal distribution of transcriptional activity downstream of canonical BMP signalling in healthy kidneys and in two distinct models of kidney disease. BRE-GFP signal coincided with expression of endogenous BMP target genes but, surprisingly, it was much more restricted than expected from the widespread distribution of pSmad1/5/8, a classical component of canonical BMP signal tranduction. BRE-GFP was mainly present in podocytes and collecting duct cells, and both glomerular and medullary BRE-GFP decreased following ischaemia-reperfusion injury as well as following unilateral ureteric obstruction, together with decreased BMP7, pSmad1/5/8 and BMP target gene expression. Remarkably, however, BRE-GFP was increased in injured proximal tubules in association with up-regulation of BMP receptors ALK2 and ALK3. Thus, native BMP transcriptional activity is much more restricted than previously suggested based on pSmad1/5/8 detection alone, and its response to injury varies according to cell type and nephron segment.
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PMID:Direct visualization of Smad1/5/8-mediated transcriptional activity identifies podocytes and collecting ducts as major targets of BMP signalling in healthy and diseased kidneys. 2138 Oct 28