Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 one of the major causative diseases leading to renal failure and dialysis treatment. Although the genetic study on the disease has been progressed so far, the initial trigger for cyst formation and several factors enhancing the progression of ADPKD remain to be clarified. Using an animal model of ADPKD, induced by 2-amino-4,5-diphenylthiazole hydrochloride (DPT), we examined the early events in cytogenesis. Especially the role of tubular obstruction in the model in triggering off tubular dilatation was investigated by means of renal micropuncture and tubular microperfusion techniques. Light and electron microscopic studies demonstrated epithelial hyperplasia along collecting ducts after 2 weeks of DPT feeding. In addition, some collecting ducts revealed partial obstruction with hyperplastic cells. Cystic change became prominent over 8 weeks of the treatment. Then micropuncture and microperfusion experiments were performed to measure intratubular pressure in the rats fed DPT for 2-5 weeks (PKD rats) and pair-fed control Sprague-Dawley rats (control rats). Free flow pressure in proximal segments of PKD rats (21.5 +/- 1.0mmHg) was not significantly elevated, as compared with that in control rats (21.3 +/- 1.0mmHg). During the stepwise increments in proximal tubular flow rate, proximal tubular pressure in PKD rats significantly increased especially at higher flow rate, 41.0 +/- 3.6 mmHg in PKD rats and 19.4 +/- 3.1mmHg in control rats (P < 0.01) at 40nl/min. On the other hand, the transit time of loop of Henle was longer in PKD rats (38.9 +/- 2.4 sec) than in control rats (24.9 +/- 0.6 sec, P < 0.01). These results suggest that cyst formation in PKD rats could be preceded by the elevation of tubular resistance, which might be explained by the partial obstruction of collecting ducts. Moreover, these tubular obstruction in the distal segments might be the trigger for the cyst formation in this model.
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PMID:[Structure and function of the experimental polycystic kidney induced by diphenylthiazole with special reference to renal micropuncture study]. 148 5

Nineteen SBM transgenic mouse lines specifically expressing the c-myc protooncogene in renal epithelium Transgene expression is completely penetrant, leading to death from renal failure. In the course of continuous breeding of eight transgenic lines, all lines underwent spontaneous transgene mutations characterized by partial deletion and probable rearrangement of the transgene insert. Revertant mice and their progeny have no evidence of renal disease. This constitutes the first report of spontaneous mutations occurring within transgene inserts. The high spontaneous mutation frequency of 10(-2) to 10(-3) greatly exceeds that of naturally occurring mutations and is probably favored by the transgene's multiple tandem insertion. These spontaneous mutations demonstrate that the intact transgene is necessary and sufficient to produce the SBM phenotype. Further, these results implicate deregulation of factor(s) governing epithelial cell proliferation in the pathogenesis of PKD in SBM mice.
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PMID:Disappearance of polycystic kidney disease in revertant c-myc transgenic mice. 819 2

In patients with symptomatic PKD who have failed medical management, surgical intervention is a reasonable option, providing long-term pain relief in the majority of patients. Individuals for whom this approach is indicated are usually narcotic dependent or disabled by pain. Cyst decompression surgery does not appear to significantly retard or arrest progressive renal insufficiency. On the other hand, widespread fears that cyst decompression might hasten renal failure are clearly unfounded. The application of newer laparoscopic techniques to this problem may allow for a wider range of symptomatic patients to realize the benefits of cyst decompression.
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PMID:Surgical management of painful polycystic kidneys. 821 92

Human autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease and displays a gender dimorphism in renal disease progression. Han:SPRD-Cy rats manifest a form of ADPKD that is similar in many respects to that seen in humans. In Han:SPRD rats, male Cy/+ rats have more prominent renal changes and develop renal failure at an early age, whereas female Cy/+ rats exhibit less severe renal cystic change and have normal renal function until advanced age. To determine whether the male gonadal hormone, testosterone, contributes to this gender dimorphism, males were sham operated or castrated; some castrated rats were repleted with 5alpha-dihydrotestosterone. Female rats were sham operated or ovariectomized before sham operation or testosterone treatment. All treatments started at 4 weeks of age and ended at 10 weeks of age. Renal enlargement, cystic change, and renal function were assessed. In the males, castration reduced renal enlargement and cystic change; testosterone treatment abrogated these effects. Neither of these manipulations affected azotemia in male Cy/+ rats. In the females, testosterone was renotropic for both normal and cystic kidneys. In the Cy/+ females, testosterone treatment caused azotemia and an increase in the severity of the PKD. Ovariectomy blunted the effect of testosterone on cystic kidney enlargement. Testosterone treatment did not completely erase the gender-associated differences in azotemia in the Cy/+ rat. These data confirm the renotropic effects of testosterone and indicate that testosterone influences the progression of renal cystic change in male and female rats with ADPKD.
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PMID:Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats. 901 99

To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 individuals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57]; II, 59 years [54, 63]; ID, 64 years [56, 72]; chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively; P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.
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PMID:Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease. 929 Nov 78

Autosomal dominant polycystic kidney disease (ADPKD) progresses to end-stage renal insufficiency before the age of 73 in approximately 48% of affected individuals. Why the disease, characterized by innumerable cysts arising in proximal and distal tubules, eliminates functioning non-cystic parenchyma in some patients and spares other is a mystery. The cysts initiate in early childhood in fewer than 1% of renal tubules as a consequence of the focal expression of mutated DNA. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of extracellular matrix proteins. Most of the cysts separate from the parent tubules and fill with fluid by cAMP-mediated chloride secretion. Risk factors associated with accelerated loss of renal function include: genotype (PKD Type 1 progresses more rapidly than PKD Type 2); gender (males progress more rapidly than females); race (black patients progress more rapidly than whites); hypertension; proteinuria. The relation between kidney size and progression to renal failure is debated. Progressive PKD is associated with the cellular expression of proto-oncogenes (fos, myc, ras, erb), growth factors (EGF, HGF, acid and basic FGF), chemokines (MCP-1. osteopontin), metalloproteinases, and apoptotic markers, and the interstitial accumulation of Types I and IV collagen, laminin, fibronectin, macrophages and fibroblasts, the magnitudes of which increase with age. Cyst activating factor (CAF), a neutral lipid identified in cyst fluid that stimulates fluid secretion and proliferation of renal epithelial cells and monocyte chemotaxis, has recently been identified as a potential progression factor. In those patients destined to develop renal failure there is loss of non-cystic parenchyma in association with mass replacement by fluid-filled cysts in a network of interstitial fibrosis. The decline in renal function is probably the consequence of processes leading to interstitial fibrosis, as in other nephropathies, rather than due to simple mechanical displacement of parenchyma by cysts.
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PMID:Mechanisms of progression in autosomal dominant polycystic kidney disease. 940 32

Sixty patients with previously documented autosomal dominant polycystic kidney disease (ADPKD) were investigated using dynamic kidney scintigraphy with 99mTc-diethylenetriaminepentaacetic acid (DTPA). Patients were subdivided in respect of glomerular filtration rate (GFR) as follows: PKD I group (normal GFR), PKD II group (moderately reduced GFR), and PKD III (severely reduced GFR). Scintigraphic features, time activity curves, excretion parameters, global and individual kidney functions were analyzed. Because of GFR dependent sensitivity, in advanced renal failure being only 0.1, and low reproducibility (11% intraobserver, 22% interobserver), 99mTc-DTPA dynamic kidney scintigraphy cannot be generally recommended for the diagnosis of ADPKD, but has to become a routine method for functional evaluation of both global and individual renal functions, as well as degree of excretion disturbances in ADPKD patients.
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PMID:Evaluation of autosomal dominant polycystic kidney disease by DTPA renal scintigraphy. 1019 76

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but devastating inherited disease in humans. Various strains of mice that are homozygous for the cpk gene display renal pathology similar to that seen in human ARPKD. The PKD progresses to renal insufficiency, azotemia, and ultimately a uremic death by approximately 3 wk of age. This study characterizes PKD in mice that are homozygous for the cpk gene on a BALB/c inbred mouse background. The BALB/c-cpk/cpk murine model displays renal as well as extrarenal pathology similar to that found in human ARPKD. The renal pathology includes the well-characterized early proximal tubule and, later, massive collecting duct cysts. The extrarenal defects in this murine model include common bile duct dilation, intrahepatic biliary duct cysts with periductal hyperplasia, and pancreatic dysplasia with cysts. Renal mRNA expression of c-myc, a proto-oncogene, and clusterin (SGP-2), a marker associated with immature collecting ducts, decreases during normal development but is upregulated in murine ARPKD. Expression of epidermal growth factor (EGF) mRNA is significantly diminished, whereas EGF receptor mRNA is upregulated in the BALB/c-cpk/cpk kidney compared with phenotypically normal littermates. To determine whether the altered EGF expression contributes to the development of PKD, neonatal mice were treated with exogenous EGF (1 microg/g body wt injected subcutaneously on postnatal days 3 through 9). EGF treatment reduced the relative kidney weight and common bile duct dilation and downregulated renal expression of clusterin and EGF receptor. However, exogenous EGF did not affect the degree of renal failure, the pancreatic pathology, or the misregulated renal expression of c-myc. In summary, the present study characterizes the renal and extrarenal pathology in the BALB/c-cpk/cpk murine model of ARPKD. Renal mRNA expression of EGF is diminished in this mouse model. EGF treatment did not prevent renal failure but ameliorated pathologic changes in the kidney and the biliary ducts of the BALB/c-cpk/cpk mouse.
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PMID:Development of autosomal recessive polycystic kidney disease in BALB/c-cpk/cpk mice. 1100 14

Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predictintegral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation.
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PMID:The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease. 1121 7

Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1-3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the Caenorhabditis elegans PKD1 and PKD2 homologs, lov-1 [5] and pkd-2, act in the same pathway in vivo. Mutations in either lov-1 or pkd-2 result in identical male sensory behavioral defects. Also, pkd-2;lov-1 double mutants are no more severe than either of the single mutants, indicating that lov-1 and pkd-2 act together. LOV-1::GFP and PKD-2::GFP are expressed in the same male-specific sensory neurons and are concentrated in cilia and cell bodies. Cytoplasmic, nonnuclear staining in cell bodies is punctate, suggesting that one pool of PKD-2 is localized to intracellular membranes while another is found in sensory cilia. In contrast to defects in the C. elegans autosomal recessive PKD gene osm-5 [6-8], the cilia of lov-1 and pkd-2 single mutants and of lov-1;pkd-2 double mutants are normal as judged by electron microscopy, demonstrating that lov-1 and pkd-2 are not required for ultrastructural development of male-specific sensory cilia.
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PMID:The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. 1155 27


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