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 (ADPKD) is a common inherited disorder frequently associated with renal failure, hypertension, and other abnormalities. The present study determined whether chronic caffeine intake in an animal model of this disease would affect renal structure and function and blood pressure. Heterozygous male Han:Sprague-Dawley rats with ADPKD and normal littermates were provided with either tap water or solutions of caffeine to drink, starting at 1 month of age. When rats were aged 6 months, glomerular filtration rate (GFR) and mean arterial blood pressure (MAP) were measured under Inactin (Byk Gulden, Konstanz, Germany) anesthesia. Caffeine intake had no effect on GFR or cyst development in rats with PKD. MAP was greater in rats with PKD than normal rats and was increased more by caffeine. The hypertensive effect of chronic caffeine intake could not be ascribed to direct pressor effects of angiotensin II. Based on our finding that caffeine exacerbates hypertension in rats with PKD, it may be prudent for patients with ADPKD to limit coffee consumption to four or fewer cups of caffeinated coffee per day, pending studies of humans.
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PMID:Chronic caffeine consumption exacerbates hypertension in rats with polycystic kidney disease. 1168 64

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

I want to thank the organizers for inviting me to present the Jeremiah Metzger Lecture at this, the 114th meeting of the ACCA. It is a high honor, indeed, to join a list of very distinguished predecessors. And for this opportunity to tell you about my passion in medicine and science, I am most grateful. Most of you in this room have passing knowledge of polycystic kidney disease, probably hearing about it in your medical school Pathology course where you were shown an especially grotesque, enormously enlarged kidney either encased in transparent plastic or submerged in a bucket of formaldehyde. In that minute or two when PKD was discussed in lecture, you may have been told that this is a rare, hereditary disorder that causes kidney failure and that nothing can be done to alter that course. Unless you chose to specialize in General Internal Medicine or Nephrology, you may not have encountered PKD again until today, despite the fact there are approximately 600,000 PKD patients in the USA and over 10,000,000 worldwide, and it accounts for approximately 5% of non-diabetic dialysis and renal transplant patients (Table 1). I might have overlooked PKD as well had it not been for a close friend that I grew up with who had inherited the disease from his mother. He was very open about the fact that he had cysts in his kidneys that caused bleeding into the urine from time to time, especially after a solid hit during a game of tackle football. We remained friends long after I left home for college and medical school. At an early stage of my research career in medicine, while wondering how nephron segments processed glomerular filtrate, I inadvertently discovered that renal tubules could secrete as well as reabsorb salt and water. This was quite an unexpected finding at the time (1). But it occurred to [table: see text] me that this might be a means to fill renal cysts with fluid and so I decided to learn more about the pathology and pathogenesis of PKD. This didn't take long, because there wasn't much literature on the subject. The clinical manifestations of PKD were described in the 19th century European medical literature and Sir William Osler had published on the topic in this country, but by and large only a few descriptions of small groups of patients were reported through the middle of the 20th century. In 1957, Dalgaard (2) reported in a classic doctoral thesis that the most common type of hereditary PKD is transmitted as an autosomal dominant trait (ADPKD) with complete penetrance. It is a bilateral renal condition, but cysts also occur in the liver (approximately 60%), pancreas (approximately 10%) and various other organs, and it is associated with cerebral aneurysms in approximately 5% of patients. A recessive form that affects infants and children primarily (ARPKD), is much rarer than ADPKD and commonly leads to death in infancy in association with massively enlarged kidneys (Table 2). I was also attracted to the study of PKD because the etiology was not in question: it had to be mutated DNA. Yet that fact proved to be a hindrance in attaining research support. As some of you will recall, not too long ago genetic diseases were viewed by kidney-oriented NIH review panels to be incurable. I was advised that a young scientist's time would be better spent determining how the kidneys excrete salt and water. Fortunately, the era of molecular genetics and biology was upon us, and we quickly learned that uncommon genetic disorders could lead to the discovery of novel molecules in metabolic and structural pathways. And that is just what happened in the PKD field. The autosomal dominant form of PKD led to the discovery of a unique family of highly complex proteins long before they would have been selected from a gene or proteomic micro-array by some desperate graduate student or fellow. The chromosomal location of the major ADPKD genotype, PKD1, was defined in 1985 (3), a date that marks the beginning of a remarkable period of discovery.
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PMID:The Jeremiah Metzger Lecture. Polycystic kidney disease: old disease in a new context. 1205 11

The kallikrein-kinin system (KKS) was investigated in autosomal dominant polycystic kidney disease (ADPKD)-affected rats (PKD) and compared to unaffected controls (SD) and 5/6 nephrectomized rats (5/6 Nx). In addition, patients with ADPKD compared to patients with nonpolycystic kidney disease and healthy controls have been investigated. Plasma and urine samples for determination of creatinine, protein, kallikrein (KAL) and bradykinin (BK) were taken in male 3- and 9-month-old PKD, SD and 9-month-old 5/6 Nx. The same parameters were determined in young (age: 20-40 years) and old (41-65 years) male patients with ADPKD and compared to age-matched patients with nonpolycystic kidney disease and age-matched healthy controls. Plasma and urine KAL were measured by chromogenic peptide substrate, and kininswere determined by radioimmunoassay. Urine KAL and BK levels were increased i n PKD compared to age-matched SD. No differences with respect to serum KAL were found between PKD and SD. In 5/6 Nx, urinary BK levels showed a trend towards higher compared to old SD (p = 0.06). KAL and BK were not increased in serum and urine of patients with ADPKD, in contrast to rats. Urinary KAL excretion was reduced in patients with ADPKD and advanced renal failure. Our results demonstrate an age-dependent activation of the renal KKS in rats with ADPKD, whereas the KKS is not activated in patients with ADPKD and advanced renal failure. These data indicate that there are fundamental differences in the factors influencing the course of the disease in human and rat ADPKD.
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PMID:Increased activity of the renal kallikrein-kinin system in autosomal dominant polycystic kidney disease in rats, but not in humans. 1248 8

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

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder in humans that causes the formation of fluid-filled renal cysts, often leading to renal failure. PKD1 mutations cause 85% of ADPKD. Feline PKD is autosomal dominant and has clinical presentations similar to humans. PKD affects approximately 38% of Persian cats worldwide, which is approximately 6% of cats, making it the most prominent inherited feline disease. Previous analyses have shown significant linkage between the PKD phenotype and microsatellite markers linked to the feline homolog for PKD1. In this report, the feline PKD1 gene was scanned for causative mutations and a C>A transversion was identified at c.10063 (human ref NM_000296) in exon 29, resulting in a stop mutation at position 3284, which suggests a loss of approximately 25% of the C-terminus of the protein. The same mutation has not been identified in humans, although similar regions of the protein are truncated. The C>A transversion has been identified in the heterozygous state in 48 affected cats examined, including 41 Persians, a Siamese, and several other breeds that have been known to outcross with Persians. In addition, the mutation is segregating concordantly in all available PKD families. No unaffected cats have been identified with the mutation. No homozygous cats have been identified, supporting the suggestion that the mutation is embryonic lethal. These data suggest that the stop mutation causes feline PKD, providing a test to identify cats that will develop PKD and demonstrating that the domestic cat is an ideal model for human PKD.
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PMID:Feline polycystic kidney disease mutation identified in PKD1. 1546 59

Nephronophthisis (NPHP), an autosomal-recessive cystic kidney disease, is the most frequent genetic cause of end-stage renal failure in children. NPHP types 1 and 4 are caused by mutations in NPHP1 and NPHP4, encoding the proteins nephrocystin-1 and nephrocystin-4, respectively. Nephrocystin-1 and nephrocystin-4 are expressed in primary cilia of renal epithelial cells. NPHP1 and NPHP4 are highly conserved in Caenorhabditis elegans. However, this species does not have a kidney but an excretory system that consists of an excretory cell, an excretory gland cell, a duct cell, and a pore cell. Therefore, cell type-specific expression pattern and function of the nephrocystin homologs in C. elegans were of interest. Expression of green fluorescence protein fusion constructs that contain the C. elegans promoter regions for nph-1 and nph-4 was not found in the excretory system but in ciliated sensory neurons of the head (amphid neurons) and the tail in hermaphrodites (phasmid neurons) and males (sensory ray neurons). As the knockout phenotype for the PKD homologs lov-1 and pkd-2 shows impaired male mating behavior, RNAi knockdown animals were analyzed for this phenotype. A similar phenotype was found in the nph-1 and nph-4 RNAi knockdown animals compared with the lov-1 and pkd-2 knockout phenotype. Thus, it is suggested that renal cyst-causing genes may be part of a shared functional module, highly conserved in evolution. The NPHP homologs may be necessary for initial assembly of the cilium, whereas the polycystic kidney disease homologs may function as sensory transducers.
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PMID:Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans. 1565 64

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

The pathogenetic mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) remain to be elucidated. While there is evidence that Pkd1 gene haploinsufficiency and loss of heterozygosity can cause cyst formation in mice, paradoxically high levels of Pkd1 expression have been detected in the kidneys of ADPKD patients. To determine whether Pkd1 gain of function can be a pathogenetic process, a Pkd1 bacterial artificial chromosome (Pkd1-BAC) was modified by homologous recombination to solely target a sustained Pkd1 expression preferentially to the adult kidney. Several transgenic lines were generated that specifically overexpressed the Pkd1 transgene in the kidneys 2- to 15-fold over Pkd1 endogenous levels. All transgenic mice reproducibly developed tubular and glomerular cysts and renal insufficiency and died of renal failure. This model demonstrates that overexpression of wild-type Pkd1 alone is sufficient to trigger cystogenesis resembling human ADPKD. Our results also uncovered a striking increased renal c-myc expression in mice from all transgenic lines, indicating that c-myc is a critical in vivo downstream effector of Pkd1 molecular pathways. This study not only produced an invaluable and first PKD model to evaluate molecular pathogenesis and therapies but also provides evidence that gain of function could be a pathogenetic mechanism in ADPKD.
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PMID:Overexpression of PKD1 causes polycystic kidney disease. 1644 63

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest inherited human disorders yet remains relatively unknown to the wider medical, scientific and public audience. ADPKD is characterised by the development of bilateral enlarged kidneys containing multiple fluid-filled cysts and is a leading cause of end-stage renal failure (ESRF). ADPKD is caused by mutations in two genes: PKD1 and PKD2. The protein products of the PKD genes, polycystin-1 and polycystin-2, form a calcium-regulated, calcium-permeable ion channel. The polycystin complex is implicated in regulation of the cell cycle via multiple signal transduction pathways as well as the mechanosensory function of the renal primary cilium, an enigmatic cellular organelle whose role in normal physiology is still poorly understood. Defects in cilial function are now documented in several other human diseases including autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome and many animal models of polycystic kidney disease. Therapeutic trials in these animal models of polycystic kidney disease have identified several promising drugs that ameliorate disease severity. However, elucidation of the function of the polycystins and the primary cilium will have a major impact on our understanding of renal cystic diseases and will create exciting new opportunities for the design of disease-specific therapies.
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PMID:Molecular pathogenesis of autosomal dominant polycystic kidney disease. 1651 28


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