Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of intracellular and extracellular pH on potassium conductance (GK) was examined in isolated amphibian (Rana pipiens) proximal tubule cells under whole cell voltage clamp conditions. Internal perfusion of the patch pipette was used to precisely control intracellular pH. In the region of normal resting potential (-51 +/- 3 mV), raising cell pH from 6.5 to 8.0 did not significantly increase GK (1.1 +/- 0.3 vs. 1.3 +/- 0.3 nS; P > 0.08, n = 8). Similar elevations in external (bath) pH had even less of an effect on GK. In contrast, when cells were voltage clamped to 30 mV more negative than the resting potential, raising internal pH from 6.5 to 8.0 did increase GK from 1.05 +/- 0.3 to 1.8 +/- 0.5 nS (P < 0.04; n = 8). These results suggest that modest changes in pH have little effect on GK, except at large negative potentials. In the process of examining the pH dependence of GK, a slowly activating, voltage-dependent conductance of 7.5 +/- 1 nS (n = 20; for 20 microns cells) was observed during cell depolarization. Although the instantaneous current-voltage relation of this conductance was linear, its marked voltage dependence produced an apparent steady-state rectification, with Gm = 0.5 +/- 0.2 nS and Gout = 9.0 +/- 1 nS (n = 11). Outward current was reversibly blocked by 3 mM Cu, Cd, or Co. In the absence of Na, K, and Ca (and only trace amounts of Cl), rapid changes in bath pH from 6.5 to 8.0 shifted the steady-state reversal potential (Erev) by -37 +/- 4 mV (n = 9) and the instantaneous Erev by -56 +/- 4 mV (n = 9). These shifts in Erev were consistent with a hydrogen ion conductance (GH), similar to what has been reported for snail neuron, neutrophils, alveolar epithelial cells, and phagocytes. Since the magnitude of this GH would be insignificant at resting cell pH and membrane potential, its role in renal proximal tubule under normal conditions is somewhat obscure. Nonetheless, in pathological situations, GH could function to prevent acid overload during any process that depolarizes the cell, such as low temperature or metabolic inhibition.
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PMID:Effect of pH on potassium and proton conductance in renal proximal tubule. 757 77

1. The following study describes the properties of a non-selective cation channel, which has a unit conductance below the resolving power of the single channel technique, located on the basolateral membrane of single proximal tubule cells isolated from frog kidney. The conductance was examined using cell-attached, inside-out and outside-out patches. Due to the small single channel magnitude, macroscopic patch currents were measured. 2. Addition of 2 mM ATP to the intracellular surface of excised patches activated an outwardly rectifying conductance (MCANS): outward (Gout) and inward (Gin) conductances increased by 46.8 +/- 6.7 and 11.6 +/- 2.1 pS, respectively (n = 29). MCANS was more selective for cations than anions, with a cation:anion selectivity ratio of 10.1 +/- 1.7 (n = 7), but did not discriminate between Na+ and K+. It was more selective for Ca2+ over Na+, with a Ca2+:Na+ selectivity ratio of 4. 49 +/- 0.69 (n = 7). 3. In cell-attached patches addition of 100 microM strophanthidin to the bath increased both Gout and Gin. However this increase in conductance was absent in the presence of Gd3+, which inhibits MCANS. 4. These data suggest that single proximal tubule cells isolated from frog kidney contain an ATP-activated, non-selective cation conductance. The conductance does not discriminate between Na+ and K+, but is more selective for Ca2+ over Na+. Considering the prevailing electrochemical gradients for these ions, functional activation of the conductance would be expected to lead to a rise in intracellular Ca2+. MCANS is linked to the activity of the Na+, K+-ATPase and may therefore provide a link between the ATPase and K+ channel activity in the basolateral membrane and form an integral part of the pump-leak mechanism in transporting epithelia.
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PMID:An intracellular ATP-activated, calcium-permeable conductance on the basolateral membrane of single renal proximal tubule cells isolated from Rana temporaria. 1069 76

Chronic lead poisoning may cause hypertension, gout, and renal insufficiency. Most experimental poisoning studies have involved the use of high doses over short periods (ie, acute poisoning). Although chelating treatment leads to remission of acute lead nephropathy, its effects in the treatment of chronic poisoning are unclear. The aims of this study were to evaluate renal alterations produced during chronic lead poisoning and their progression when poisoning was over and to determine the efficiency of chelating treatment with calcium disodium ethylenediaminetetraacetate (EDTA). In this study, 56 male Wistar rats were administered lead in drinking water (500 ppm lead acetate) over 90 days. The control group consisted of 21 nonexposed rats. Seven rats from each group were killed on days 60 and 90. At the end of the 90-day period, 21 of the lead-exposed rats were treated with disodium monocalcium EDTA (50 mg/kg/d x 5 days) intraperitoneally, and 21 were administered serum saline by the same route. Three treatment courses were given separated by 9 days free of treatment. Seven rats from each subgroup were sacrificed at the end of each treatment course. Main findings related to poisoning were hypertrophy and vacuolization of medium and small arteries; mucoid edema and muscular hypertrophy in arterioles; loss of cell brush borders, cell loss, and intranuclear inclusion bodies in the proximal tubule; and fibrosis and the presence of infiltrates in the interstitial component. Treatment with EDTA slowed the progression of most alterations. No damage associated with the use of the chelating agent was observed. Longer term studies of the effects of this drug are required to establish whether the damage caused by lead poisoning may be reversed.
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PMID:Experimental lead nephropathy: treatment with calcium disodium ethylenediaminetetraacetate. 1208 80

Humans excrete uric acid as the final breakdown product of unwanted purine nucleotides. Urate scavenges potential harmful radicals in our body. However, in conjunction with genetic or environmental (especially dietary) factors, urate may cause gout, nephrolitiasis, hypertension, and vascular disease. Blood levels of urate are maintained by the balance between generation and excretion. Excretion requires specialized transporters located in renal proximal tubule cells, intestinal epithelial cells, and vascular smooth muscle cells. The recently identified human urate transporters URAT1, MRP4, OAT1, and OAT3 are thought to play central roles in homeostasis and may prove interesting targets for future drug development.
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PMID:Molecular physiology of urate transport. 1577 1

Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination. The kidney excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the under excretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.
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PMID:Renal urate handling: clinical relevance of recent advances. 1591

Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.
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PMID:Gout in 2006: the perfect storm. 1712 96

Colchicine has been used to control gouty arthritis for long time; colchicine overdose, however, causes multiple organ dysfunction. To date, no investigation has revealed the site of kidney lesion or dysfunction. This investigation describes the case of a male with a history of gout who ingested a large amount of colchicine and developed renal, hematopoietic, gastrointestinal, muscular, electrolytic, and hepatic disorder. Glucosuria was noted during hospital days. Colchicine intoxication is shown to induce proximal tubule damage. Severe electrolytes imbalance was noted, including hypomagnesemia, hypophosphatemia, and hypocalcemia. After management, the renal function and serum electrolyte of the patient recovered on the sixth day of hospitalization.
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PMID:Colchicine overdose-induced acute renal failure and electrolyte imbalance. 1749 54

In highly industrialized countries hyperuricemia is one of the most common metabolic disorders. High uric acid blood levels may lead to the manifestation of gout owing to the precipitation of urate crystals in connective tissue, the skeletal system and kidneys. A primary reduction of renal uric acid excretion can be detected in more than 90% of all cases of hyperuricemia. Despite the identification of several uric acid transporting proteins their pathogenetic role for the induction of primary reduced renal uric acid excretion has not yet been verified. As a result of a case-control study on individuals with normal and reduced renal uric acid excretion, an association of polymorphisms in the human urate transporter 1 gene (hURAT1) with primary reduced urate excretion has been demonstrated for the first time. The hURAT1 gene is an organic anion transporter (SLC22A12), which is preferentially expressed in the apical membrane of proximal renal tubule cells. Functioning as an antiporter, hURAT1 mediates the uptake of urate from the lumen into proximal tubule cells in exchange for organic and inorganic anions. Loss-of-function mutations in the hURAT1 gene are a cause of hereditary renal hypouricemia. The precisely regulated hURAT1 is a candidate gene for hyperuricemia and an important target for the development and optimization of new diagnostic approaches and pharmacological interventions of primary reduced renal uric acid excretion.
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PMID:[Molecular basis of primary renal hyperuricemia : role of the human urate transporter hURAT1]. 1789 8

Cadmium and lead are divalent cations with a propensity to settle in the proximal tubule of the nephron, leading to nephrotoxicity. The pathophysiological results, however, tend to diverge. Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout, presumably by inhibiting uric acid secretion, and diminished glomerular filteration rate (GFR). Fanconi syndrome is seen unusually only in children and experimental animals. Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function. Beta2-microglobulinuria is not found in lead nephropathy. In lead nephropathy albuminuria is absent or minimal whereas in cadmium nephropathy albuminuria is variable. From the standpoint of pathology, both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein.
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PMID:Nephrotoxicity of cadmium & lead. 1910 33

Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels [whites: P = 10(-30), minor allele frequency (MAF) 0.11; blacks P = 10(-4), MAF 0.03] and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.
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PMID:Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. 1950 52


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