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)

The recent discovery of mutations in the uromodulin gene ( UMOD ) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD -related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations.
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PMID:Uromodulin storage diseases: clinical aspects and mechanisms. 1555 19

We assayed the redox forms of cysteine (reduced [CSH], oxidized [CSSC], and bound to protein [CS-SP]), cysteinylglycine (CGSH; cysteinylgycine disulfide [CGSSGC] and cysteinylglycine-protein mixed disulfide [CGS-SP]), glutathione (GSH; glutathione disulfide [GSSG] and glutathione-protein mixed disulfide [GS-SP]), homocysteine (Hcy; homocystine [HcyS] and homocystine-protein mixed disulfides [bHcy]), and protein sulfhydryls in the plasma of healthy subjects (divided into 8 groups ranging in age from birth to 70 years) and patients with mild hyperhomocysteinemia associated with cardiovascular disease (heart-transplant patients) or vascular atherosclerosis, with or without renal failure. In healthy individuals, levels of disulfides and protein-mixed disulfides were more abundant than those of thiols, and those of protein-thiol mixed disulfides were higher than disulfides. Concentrations of CSH, GSH, and CGSH in the various groups had profiles characterized by a maximum over time. The concentration of Hcy was unchanged up to the age of 30 years, after which it increased. CSSC concentration increased gradually with age, whereas concentrations of the other disulfides were essentially unchanged. By contrast, the concentrations of all protein-thiol mixed disulfides, especially those with CSH, increased gradually with age. Ranks of distribution of the reduced forms changed with age (at birth, CSH > CGSH > GSH > Hcy; in 1- to 2-year-olds, CSH > GSH > CGSH > Hcy; and in 51- to 70-year-olds, CSH > CGSH = GSH > Hcy), whereas those of disulfides and protein-thiol mixed disulfides were substantially unchanged (in all age groups, CSSC > CGSSGC > GSSG = HcyS and CS-SP > CGS-SP > bHcy > GS-SP). In patients with pathologic conditions, plasma levels of disulfide forms CSSC, HcyS, CS-SP, and bHcy were significantly increased, whereas other redox forms of thiols were unchanged or showed variations opposite (increasing or decreasing) to control values. Maximal increases in disulfides and protein-thiol mixed disulfides were associated with renal failure. Our data suggest that increases in plasma bHcy concentrations in subjects with pathologic conditions were more likely the result of activation of thiol-disulfide exchange reactions between free reduced Hcy and CS-SP than of a direct action of reactive oxygen species.
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PMID:The effects of age and hyperhomocysteinemia on the redox forms of plasma thiols. 1557 Feb 41

Renal insufficiency is invariably accompanied by elevated plasma concentrations of the sulfur-containing and potentially vasculotoxic amino acid homocysteine. There is a strong relationship between glomerular filtration rate and plasma homocysteine concentration. Unlike creatinine, however, homocysteine is avidly reabsorbed in the renal tubules, and its urinary excretion is minimal. There is no evidence that homocysteine is actively removed by the human kidney. In renal insufficiency, plasma concentrations of S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, and sulfate are elevated, pointing to a remethylation or distal transsulfuration/oxidation block as the cause of hyperhomocysteinemia in renal failure. Stable isotope techniques have shown that both whole-body homocysteine remethylation and methionine transmethylation are decreased in renal failure, whereas homocysteine transsulfuration seems intact. Metabolic homocysteine clearance (i.e., transsulfuration relative to plasma homocysteine) is decreased to a major extent. These metabolic disturbances in renal failure can only be partially restored with current treatments. Folic acid treatment lowers plasma homocysteine concentration and increases remethylation and transmethylation rates. Plasma homocysteine, however, is not normalized, and metabolic homocysteine clearance by transsulfuration remains impaired. According to the currently available data, effective normalization of plasma homocysteine can only be obtained when its metabolic clearance through transsulfuration is restored.
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PMID:Homocysteine and methionine metabolism in renal failure. 1604 72

The role of hyperhomocysteinemia (HHcy) as a risk marker for cardiovascular diseases in renal patients is a matter of controversy. The remethylation of homocysteine (Hcy) to methionine in the kidneys is of great importance for Hcy clearance. Hcy remethylation is markedly decreased in patients on hemodialysis, but transsulfuration remains mostly unaffected. Markedly increased concentrations of methylmalonic acid (MMA), as a metabolic marker of vitamin B12 deficiency, have been found in approximately 70% of renal patients. This is in contrast to normal concentrations of vitamin B12 usually reported in such patients. We demonstrated in cell culture experiments that the uptake of vitamin B12 by mononuclear cells from renal patients was lower than that taken up by cells from controls. The lowering of MMA and Hcy concentrations in renal patients after B12 administration may indicate the presence of intracellular pre-treatment deficiency. We administered folic acid (5 mg) plus vitamin B6 (50 mg) and B12 (0.7 mg) three times per week intravenously to hyperhomocysteinemic dialysis patients. Hcy decreased after 4 weeks by 51%. Hcy was normalized in almost all patients, while serum concentrations of MMA and cystathionine were reduced by 28% and 26%, respectively. Cystathionine, an indicator for the transsulfuration pathway, showed a drastic increase in renal disease and was only slightly lowered by B-vitamin treatment. The increased cystathionine/cysteine ratio in renal patients indicates possible impairment of the catabolism of cystathionine by cystathionase. Moreover, renal failure is associated with severe abnormalities in plasma concentrations of S-adenosyl Hcy (SAH) and S-adenosyl methionine (SAM), as well as the SAM/SAH ratio. This ratio is an indicator of the availability of methyl groups from SAM. Therapeutic doses of B-vitamins in dialysis patients led to a limited improvement in the biomarkers of methylation and probably did not have a significant effect on transmethylation potential in the cells. Furthermore, elevated serum levels of asymmetric dimethylarginine (ADMA) in renal patients, which are associated with a poor outcome for such patients, could be lowered, but this effect was confined to patients who had no anemia. Future studies may consider extending the duration of vitamin treatment, as well as agents that may enhance the hydrolysis of SAH and cystathionine.
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PMID:Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients. 1619 95

Plasma homocysteine (Hcy) levels are increased significantly in patients with moderate renal failure and increase markedly in patients with end-stage renal disease. An increase in plasma Hcy level theoretically could be caused by an increased production rate (ie, transmethylation), a decreased rate of removal by transsulfuration or remethylation, or a decrease in the excretion of Hcy. Current evidence indicates that the major mechanism for hyperhomocysteinemia in renal failure is a decrease in Hcy removal from the body. However, it is debated whether this effect is the result of a decrease in the renal metabolic clearance or a result of extrarenal metabolic changes. The human kidney plays a major role in the removal of several aminothiols or Hcy-related compounds from the circulation (eg, cysteine-glycine, glutathione, AdoMet, and AdoHcy). However, the glomerular filtration of Hcy seems to be restricted because of protein binding. Besides glomerular filtration, the normal kidney can remove Hcy by plasma flow and peritubular uptake. Although in the low normal range in absolute terms, the flow through the transsulfuration pathway is reduced if related to Hcy levels in uremia; in addition, the remethylation pathway also is impaired. Besides the potential effect of the reduced renal mass on Hcy removal, available evidence suggests the occurrence of a generalized down-regulation of the methionine cycle and catabolism in uremia. AdoHcy, sulfate, and dimethylglycine currently are being investigated as retained solutes that can inhibit 1 or more pathways of Hcy metabolism. In addition, the high Hcy levels decrease in malnourished end-stage renal disease patients and change according to nutrient intake and several other nutritional parameters, indicating that circulating Hcy levels become an expression of nutritional status.
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PMID:Causes of hyperhomocysteinemia in patients with chronic kidney diseases. 1641 17

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.
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PMID:Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. 1714 84

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Recent work has suggested a role of p53 in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study determined the possible involvement of oxidative stress in p53 activation under the pathological condition using in vitro and in vivo models. In cultured renal proximal tubular cells, cisplatin at 20 microM induced an early p53 phosphorylation followed by protein accumulation. Cisplatin also induced reactive oxygen species (ROS), among which hydroxyl radicals showed a rapid and drastic accumulation. Dimethylthiourea (DMTU) and N-acetyl-cysteine (NAC) attenuated hydroxyl radical accumulation, and importantly, diminished p53 activation during cisplatin treatment. This was accompanied by the suppression of PUMA-alpha, a p53-regulated apoptotic gene. Concomitantly, mitochondrial cytochrome c release and apoptosis were ameliorated. Notably, DMTU and NAC, when added post-cisplatin treatment, were also inhibitory to p53 activation and apoptosis. In C57BL/6 mice, cisplatin at 30 mg/kg induced p53 phosphorylation and protein accumulation, which was also abrogated by DMTU. DMTU also ameliorated tissue damage, tubular cell apoptosis and cisplatin-induced renal failure. Collectively, this study has suggested a role of oxidative stress, particularly hydroxyl radicals, in cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity.
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PMID:Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. 1729 59

Conditions in which serum or tissue acrolein levels are high (e.g.: renal failure, heavy smoking, oxidative stress) are also associated with increased thrombogenicity. Another emerging cardiovascular risk factor is homocysteine, and its derivative, homocysteine thiolactone. Antithrombin is one of the most important inhibitors of blood coagulation Since its activation by heparin binding requires critical interactions involving 3 Lys residues; we hypothesized that acrolein or homocysteine thiolactone impair antithrombin activity. When we incubated human antithrombin with increasing concentrations of acrolein (0-2 mmol/L) over a short period of time (0-4 h), a time and concentration dependent loss of activity was apparent (IC(50)=0.25 mmol/L). At 2 mmol/L, maximum inhibition (60%) is achieved at 1 h. This loss of activity was mirrored by changes in the electrophoretic pattern (homogeneity of the native antithrombin band as well as polymerization). In the same conditions, homocysteine thiolactone produces a significant, yet far less pronounced effect; acrolein being 3 times more potent than homocysteine thiolactone. When antithrombin was co-incubated with acrolein and cysteine, only less than 10% of antithrombin activity was lost. Aminoguanidine or carnosine displayed a significant yet, minor protective effect. The results suggest that in conditions where circulating or local acrolein concentrations are increased (atheroma plaque, thrombosis, sites of lipoperoxidation, smokers), acrolein-mediated loss of antithrombin activity could be a plausible phenomenon. This could contribute to explain increased thrombogenicity in smokers and in other conditions, as well as pointing at dietary intervention or the use of thiol-conserving reducing compounds as putative coadjuvant therapeutic measures.
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PMID:Antithrombin activity is inhibited by acrolein and homocysteine thiolactone: Protection by cysteine. 1820 77

Pharmacologic interventions for the prevention and therapy of acute kidney injury (AKI) can be roughly divided into 2 main strategies: Optimising renal perfusion and modulation of intrarenal pathophysiological mechanisms, i.e. formation of free oxygen radicals, inflammation, tubular cast formation and renal (tubular) regeneration. Improvement of impaired renal perfusion can be achieved by optimising systemic haemodynamics by volume expansion and the appropriate use of inotropes and/or vasopressors. Up to now prospective randomised controlled trials on selective renal vasodilatation have turned out rather unsuccessful, with the exception of the adenosine antagonist theophylline, in certain indications like drug-induced renal failure or contrast nephropathy. Studies in humans on pharmacological interventions interfering with intrarenal pathophysiological mechanisms of AKI are also sparse. Investigated compounds comprise N-acetyl-cysteine, mannitol and antioxidants like selenium or vitamin C. The results are heterogeneous and a significant beneficial effect of either substance could not yet be convincingly demonstrated.
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PMID:Medical therapy of acute kidney injury. 1828 98

We examined the relationship between change in the redox state of the plasma albumin molecule and the metabolic disorder of sulfur amino acid observed being accompanied by reduction of renal function. Thirty-seven cases of pre-dialysis renal failure with conservative treatment and thirteen cases of chronic hemodialysis were selected as the subjects of this examination. The fraction of plasma albumin and the concentration of plasma cysteine and homocysteine were respectively measured by the HPLC and GC/MS (gas chromatography/mass spectrometry) methods. In the case of pre-dialysis renal failure with conservative treatment, the reduction rate of plasma albumin significantly decreased in correspondence with reduction of the glomerular filtration rate (GFR). It is well known that the reduction rate of plasma albumin also decreases with the aging process. However, in regard to chronic hemodialysis, a correlation with aging was not found, where the transient reduction rate of plasma albu- min increased after the hemodialysis session. However, in correspondence with the decrease in renal function, the concentration of plasma cysteine and homocysteine increased. This shows that there was a negative correlation with GFR in cases of pre-dialysis renal failure with conservative treatment. In cases of chronic hemodialysis, the concentration of free cysteine and free homocysteine rapidly decreased after a hemodialysis session. Therefore, a negative correlation was recognized between the reduction rate of plasma albumin and the concentration of plasma cysteine and homocysteine. The result of this examination shows the following mechanisms: plasma albumin plays an important role in the reaction of oxidation/reduction in blood plasma, and sulfur amino acid in blood plasma, especially the abnormality of cysteine concentration, plays an important role in changing the redox state of the blood plasma observed in the decrease in renal function.
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PMID:[Clinical evaluation of serum albumin reductivity in patients with renal dysfunction: a comparison between conservative renal failure patients and hemodialysis patients]. 1854 83


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