Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant polycystic kidney disease is a common inherited disorder, which is characterised by the formation of fluid-filled cysts in both kidneys that leads to progressive renal failure. Mutations in two genes, PKD1 and PKD2, are associated with the disorder. We describe the various factors that cause variation in disease progression between patients. These include whether the patient has a germline mutation in the PKD1 or in the PKD2 gene, and the nature of the mutation. Detection of mutations in PKD1 is complicated, but the total number identified is rising and will enable genotype-to-phenotype studies. Another factor affecting disease progression is the occurrence of somatic mutations in PKD genes. Furthermore, modifying genes might directly affect the function of polycystins by affecting the rate of somatic mutations or the rate of protein interactions, or they might affect cystogenesis itself or clinical factors associated with disease progression. Finally, environmental factors that speed up or slow down progress towards chronic renal failure have been identified in rodents.
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PMID:Autosomal dominant polycystic kidney disease: modification of disease progression. 1170 10

Mutations of either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease, a syndrome characterized by extensive formation of renal cysts and progressive renal failure. Homozygous deletion of Pkd1 or Pkd2, the genes encoding polycystin-1 and polycystin-2, disrupt normal renal tubular differentiation in mice but do not affect the early steps of renal development. Here, we show that expression of the C-terminal 112 amino acids of human polycystin-1 triggers branching morphogenesis and migration of inner medullary collecting duct (IMCD) cells, and support in vitro tubule formation. The integrity of the polycystin-2-binding region is necessary but not sufficient to induce branching of IMCD cells. The C-terminal domain of polycystin-1 stimulated protein kinase C-alpha (PKC-alpha), but not the extracellular signal-regulated kinases ERK1 or ERK2. Accordingly, inhibition of PKC, but not ERK, prevented polycystin-1-mediated IMCD cell morphogenesis. In contrast, HGF-mediated morphogenesis required ERK activation but was not dependent on PKC. Our findings demonstrate that the C-terminal domain of polycystin-1, acting in a ligand-independent fashion, triggers unique signaling pathways for morphogenesis, and likely plays a central role in polycystin-1 function.
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PMID:The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells. 1185 20

A common inherited cause of renal failure, autosomal dominant polycystic kidney disease results from mutations in either of two genes, PKD1 and PKD2, which encode polycystin-1 and polycystin-2, respectively. Polycystin-2 has distant homology to TRP cation channels and associates directly with polycystin-1. The normal functions of polycystins are poorly understood, although recent studies indicate that they are concentrated in the primary cilia of a variety of cell types. In this report we identified a polycystin-2 homolog in Drosophila melanogaster; this homolog localized to the distal tip of the sperm flagella. A targeted mutation in this gene, almost there (amo), caused nearly complete male sterility. The amo males produced and transferred normal amounts of motile sperm to females, but mutant sperm failed to enter the female sperm storage organs, a prerequisite for fertilization. The finding that Amo functions in sperm flagella supports a common and evolutionarily conserved role for polycystin-2 proteins in both motile and nonmotile axonemal-containing structures.
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PMID:A flagellar polycystin-2 homolog required for male fertility in Drosophila. 1468 Jun 34

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of renal cysts that eventually result in loss of renal function in the majority of affected individuals. The diagnosis of ADPKD is typically made using renal imaging despite the identification of mutations in PKD1 and PKD2 that account for virtually all cases. Mutations in PKD1 are associated with more severe clinical disease and earlier onset of renal failure. Most PKD gene mutations are loss of function and a 'two-hit' mechanism has been demonstrated underlying focal cyst formation. The protein products of the PKD genes, the polycystins, form a calcium-permeable ion channel complex that regulates the cell cycle and the function of the renal primary cilium. Abnormal cilial function is now thought to be the primary defect in several types of PKD including autosomal recessive polycystic kidney disease and represents a novel and exciting mechanism underlying a range of human diseases.
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PMID:Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). 1487 99

Polycystic kidney disease (PKD) is a disease of the nephron, characterized by the formation of multiple renal tubular cysts, leading to endstage renal failure. The most common form is autosomal dominant PKD (ADPKD) and is caused by mutations in the PKD1 gene in 85% of cases or in PKD2 in 10-15%. Rarer forms include autosomal recessive PKD (ARPKD) and nephronophthisis with high mortality and morbidity in children. Recent advances suggest that the PKD1-encoded protein, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment at the basal surface in focal adhesion complexes; at the lateral surface in cell adherens junctions; and in the lumen at the apical primary cilium. Activation via multiprotein complex formation, intracellular signal transduction cascades and regulation of fetal gene transcription leads to appropriate renal tubule epithelial cell division and differentiation in normal kidneys, but is disrupted in PKD resulting in cyst formation.
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PMID:Polycystic kidney disease: new understanding in the pathogenesis. 1520 99

Autosomal dominant polycystic kidney disease, characterized by extensive formation of renal cysts and progressive renal failure, is a genetic disorder caused by mutations in the PKD1 and PKD2 genes. The PKD1 gene product, polycystin-1, is a transmembrane protein with its N-terminus facing the extracellular region and C-terminus facing the cytoplasm. Polycystin-1 seems to be involved in regulating cell growth and maturation, but the precise mechanisms are not yet well defined. For investigating the function of the intracellular region of polycystin-1, the C-terminal cytoplasmic fragment of polycystin-1, PKD1-C, was used as bait in two-hybrid screening, and a polycystin-1-binding protein, the human homologue of Drosophila Seven in Absentia (Siah-1), which has a RING domain and promotes the ubiquitin-dependent proteasome pathway, was identified. It was shown that PKD1-C interacts with Siah-1 in vivo. In addition, interaction with Siah-1 induces the degradation of PKD1-C, shortening its half-life. PKD1-C and CD4 chimeric proteins, which are attached to the plasma membrane, also show similar results. Furthermore, ubiquitination and degradation of PKD1-C are increased in the presence of Siah-1, and overexpression of Siah-1 protein promotes the degradation of polycystin-1 via the ubiquitin-proteasome pathway. These results suggest that polycystin-1 is regulated by Siah-1 through the ubiquitin-dependent proteasome pathway.
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PMID:Siah-1 interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway. 1528 90

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of renal failure and is characterized by the formation of many fluid-filled cysts in the kidneys. It is a systemic disorder that is caused by mutations in PKD1 or PKD2. Homozygous inactivation of these genes at the cellular level, by a 'two-hit' mechanism, has been implicated in cyst formation but does not seem to be the sole mechanism for cystogenesis. We have generated a novel mouse model with a hypomorphic Pkd1 allele, Pkd1(nl), harbouring an intronic neomycin-selectable marker. This selection cassette causes aberrant splicing of intron 1, yielding only 13-20% normally spliced Pkd1 transcripts in the majority of homozygous Pkd1(nl) mice. Homozygous Pkd1(nl) mice are viable, showing bilaterally enlarged polycystic kidneys. This is in contrast to homozygous knock-out mice, which are embryonic lethal, and heterozygous knock-out mice that show only a very mild cystic phenotype. In addition, homozygous Pkd1(nl) mice showed dilatations of pancreatic and liver bile ducts, and the mice had cardiovascular abnormalities, pathogenic features similar to the human ADPKD phenotype. Removal of the neomycin selection-cassette restored the phenotype of wild-type mice. These results show that a reduced dosage of Pkd1 is sufficient to initiate cystogenesis and vascular defects and indicate that low Pkd1 gene expression levels can overcome the embryonic lethality seen in Pkd1 knock-out mice. We propose that in patients reduced PKD1 expression of the normal allele below a critical level, due to genetic, environmental or stochastic factors, may lead to cyst formation in the kidneys and other clinical features of ADPKD.
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PMID:Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. 1549 22

Autosomal dominant polycystic kidney disease (ADPKD) is a serious, life-threatening genetic disease in which extensive epithelial-lined cysts develop in the kidneys and, to a lesser extent, in other organs such as liver, pancreas, and ovaries. In a majority of cases (80-85%), the gene involved is PKD1, which is located on chromosome 16 (16q13.3) and encodes polycystin-1, a large receptor-like integral membrane protein that contains several extracellular motifs indicative of cell-cell and cell-matrix interaction. In the remaining (10-15%) cases, the disease is milder and is caused by mutational changes in another gene (PKD2), which is located at chromosome 4 (4q21-23) and encodes polcystin-2, a transmembrane protein, which acts as a nonspecific calcium-permeable channel. Both polycystins function together in a nonredundant fashion, through a common pathway, and produce cellular responses that regulate proliferation, migration, differentiation, and kidney morphogenesis. Through combined function of polycystins, normal tubular cells are maintained in a state of terminal differentiation, and their proliferation is strictly controlled. Loss of function of either protein due to gene mutations results in the tubular cells reverting to a less differentiated state, which is more prone to proliferation. Patients with ADPKD carry a germ-line mutation in PKD1 or PKD2. A second somatic mutation in some of the tubular cells results in loss of both normal alleles, leading to loss of polycystin function. The affected cells lose the normal terminally differentiated state, revert to less differentiated phenotype, and undergo proliferation, which leads to cyst formation. As the cysts enlarge over many decades, the normal renal parenchyma is progressively destroyed, leading to renal failure. Recently, the crucial role of primary cilia in modulating proliferation, migration, and differentiation of tubular epithelium has been recognized. Most of the tubular cells have one or two primary cilia projecting from the apical surface into the luminal space. The cilia act as mechanoreceptors as they bend with the urinary flow within the tubules. Both polycystins are strategically located within the cilia and act as important mediators of ciliary mechanosensation. Loss of this important function due to mutational changes in PKD1 or PKD2 leads to loss of normal control over cellular proliferation, resulting in cyst formation. Several other ciliary proteins have recently been found to contribute directly to a wide spectrum of human kidney diseases with cystic phenotype, thus underscoring the pivotal role the primary cilia play in maintaining the normal structure and function of the tubular cells and probably other cells in the body.
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PMID:Molecular basis of autosomal dominant polycystic kidney disease. 1590 Jan 13

Autosomal dominant polycystic kidney disease (PKD) is the most common genetic disease that leads to kidney failure in humans. In addition to the known causative genes PKD1 and PKD2, there are mutations that result in cystic changes in the kidney, such as nephronophthisis, autosomal recessive polycystic kidney disease, or medullary cystic kidney disease. Recent efforts to improve the understanding of renal cystogenesis have been greatly enhanced by studies in rodent models of PKD. Genetic studies in the (cy/+) rat showed that PKD spontaneously develops as a consequence of a mutation in a gene different from the rat orthologs of PKD1 and PKD2 or other genes that are known to be involved in human cystic kidney diseases. This article reports the positional cloning and mutation analysis of the rat PKD gene, which revealed a C to T transition that replaces an arginine by a tryptophan at amino acid 823 in the protein sequence. It was determined that Pkdr1 is specifically expressed in renal proximal tubules and encodes a novel protein, SamCystin, that contains ankyrin repeats and a sterile alpha motif. The characterization of this protein, which does not share structural homologies with known polycystins, may give new insights into the pathophysiology of renal cyst development in patients.
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PMID:Missense mutation in sterile alpha motif of novel protein SamCystin is associated with polycystic kidney disease in (cy/+) rat. 1620 29

Autosomal dominant polycystic kidney disease, a common cause of renal failure, arises from mutations in either the PKD1 or the PKD2 gene. The precise function of both PKD gene products polycystins (PCs) 1 and 2 remain controversial. PC2 has been localized to numerous cellular compartments, including the endoplasmic reticulum, plasma membrane, and cilia. It is unclear what pools are the most relevant to its physiological function as a putative Ca2+ channel. We employed a Xenopus oocyte Ca2+ imaging system to directly investigate the role of PC2 in inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling. Cytosolic Ca2+ signals were recorded following UV photolysis of caged IP3 in the absence of extracellular Ca2+. We demonstrated that overexpression of PC2, as well as type I IP3 receptor (IP3R), significantly prolonged the half-decay time (t1/2) of IP3-induced Ca2+ transients. However, overexpressing the disease-associated PC2 mutants, the point mutation D511V, and the C-terminally truncated mutation R742X did not alter the t1/2. In addition, we found that D511V overexpression significantly reduced the amplitude of IP3-induced Ca2+ transients. Interestingly, overexpression of the C terminus of PC2 not only significantly reduced the amplitude but also prolonged the t1/2. Co-immunoprecipitation assays indicated that PC2 physically interacts with IP3R through its C terminus. Taken together, our data suggest that PC2 and IP3R functionally interact and modulate intracellular Ca2+ signaling. Therefore, mutations in either PC1 or PC2 could result in the misregulation of intracellular Ca2+ signaling, which in turn could contribute to the pathology of autosomal dominant polycystic kidney disease.
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PMID:Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. 1622 35


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