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)

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
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PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

RAGE (receptor for advanced glycation end products) is a multiligand cell surface molecule of the immunoglobulin superfamily. It was originally described as a receptor for protein adducts formed by glycoxidation (AGEs) that accumulate in diseases such as diabetes and renal failure. Performing RT-PCR and Western blot analysis we intended to determine RAGE expression in the human colon adenocarcinoma cell line Caco-2. Moreover, Caco-2 cells were incubated in the presence of AGEs. Since RAGE ligation triggers the p21(ras) signal transduction pathway the activation state of p44/42 (ERK1/2) MAP kinases was determined. Here we demonstrate for the first time that Caco-2 cells express RAGE and that administration of the food-derived casein-linked AGE N(epsilon)-(carboxymethyl)lysine (Cas-CML) results in Caco-2 p44/42 (ERK1/2) MAP kinase activation.
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PMID:RAGE expression and AGE-induced MAP kinase activation in Caco-2 cells. 1170 25

The Wilms' tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms' tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene. This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.
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PMID:An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis. 1205 Feb 5

We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN.
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PMID:Acute interstitial nephritis due to nicergoline (Sermion). 1237 54

Advanced glycation endproduct (AGE) levels are elevated in renal failure patients and may contribute to the excessive cardiovascular disease in this population. Diet-derived AGE are major contributors to the total body AGE pool. It was postulated that a reduction in dietary AGE intake might impact on the high circulating AGE levels in renal failure patients. Twenty-six nondiabetic renal failure patients on maintenance peritoneal dialysis were randomized to either a high or a low AGE diet for 4 wk. Three-day dietary records, fasting blood, 24-h urine, and dialysis fluid collections were obtained at baseline and end of study. AGE levels were determined by ELISA for N(epsilon)-carboxymethyl-lysine (CML) and methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low dietary AGE intake decreased serum CML (34%; P < 0.002), serum MG (35%; P < 0.008), CML-LDL (28%; P < 0.011), CML-apoB (25%; P < 0.028), dialysate CML (39%; P < 0.03), and dialysate MG output (40%; P < 0.04). High dietary AGE intake increased serum CML (29%; P < 0.028), serum MG (26%; P < 0.09), CML-LDL (50%; P < 0.011), CML-apoB (67%; P < 0.028), and dialysate CML output (27%; P < 0.01). Serum AGE correlated with BUN (r = 0.6, P < 0.002 for CML; r = 0.4, P < 0.05 for MG), serum creatinine (r = 0.76, P < 0.05 for CML; r = 0.55, P < 0.004 for MG), total protein (r = 0.4, P < 0.05 for CML; r = 0.4, P < 0.05 for MG), albumin (r = 0.4, P < 0.02 for CML; r = 0.4, P < 0.05 for MG), and phosphorus (r = 0.5, P < 0.006 for CML; r = 0.5, P < 0.01 for MG). It is concluded that dietary glycotoxins contribute significantly to the elevated AGE levels in renal failure patients. Moreover, dietary restriction of AGE is an effective and feasible method to reduce excess toxic AGE and possibly cardiovascular associated mortality.
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PMID:Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. 1259 9

Carnitine is a low-molecular-weight compound obtained from the diet that also is biosynthesized from the essential amino acids lysine and methionine. Carnitine has been identified in a variety of mammalian tissues and has an obligate role in the mitochondrial oxidation of long-chain fatty acids through the action of specialized acyltransferases. Other roles for carnitine include buffering of the acyl coenzyme A (CoA)-CoA ratio, branched-chain amino acid metabolism, removal of excess acyl groups, and peroxisomal fatty acid oxidation. The growing body of evidence about carnitine function has led to increased understanding and identification of disorders associated with altered carnitine metabolism. Disorders of fatty acid oxidation and metabolism typically are associated with primary and secondary forms of carnitine deficiency. These disorders, which include increased lipolysis, increased lipid peroxidation, accumulation of acylcarnitines, and altered membrane permeability, have significant consequences for patients with myocardial diseases and kidney failure. Therapeutic administration of carnitine shows promise in treating selected groups of patients who have altered carnitine homeostasis, resulting in improved cardiac function, increased exercise capacity, reduced muscle cramps, and reduced intradialytic complications.
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PMID:The role of carnitine in normal and altered fatty acid metabolism. 1275 Oct 49

AGEs (advanced glycation end products) accumulate markedly in the plasma of human subjects with renal failure. We investigated the efficiency of removal of AGEs from the circulation by PD (peritoneal dialysis) and HD (haemodialysis) therapy. Free AGEs were measured by LC-MS/MS in blood plasma before dialysis, in dialysis fluid effusate after a 2-12 h dwell time in the peritoneal cavity of PD subjects, and in the HD dialysate before and after HD therapy. In clinical uraemia, the concentrations of free AGEs in blood plasma were increased up to 50-fold. For example, levels of MG-H1 (methylglyoxal-derived hydroimidazolone) were: normal controls, 110+/-46 nM; PD subjects, 1876+/-676 ( P <0.01); HD subjects, 5496+/-1138 nM ( P <0.001). In PD subjects, the AGE concentration in the effusate increased with increasing dwell time, reaching a maximum at a concentration higher than that in plasma for some AGEs at 4-12 h. This may reflect AGE formation in the peritoneal cavity. In HD, AGE concentrations in HD fluid were decreased markedly from the start to the end of a dialysis session, except that levels of the methylglyoxal-derived AGEs N (epsilon)-(1-carboxyethyl)lysine and MG-H1, and of pentosidine, remained 5-fold higher than control levels. Inadequate clearance of free AGEs may be linked to the increased risk of cardiovascular disease in patients with renal failure.
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PMID:Removal of advanced glycation end products in clinical renal failure by peritoneal dialysis and haemodialysis. 1464 Oct 71

The term "advanced glycation end products" (AGEs) stands for a heterogeneous group of amino acid derivatives that are formed via glycation processes between peptide-bound lysine or arginine derivatives and carbonyl compounds, processes originally known from food systems as "Maillard reactions." AGEs accumulate in plasma and tissues with advancing age, diabetes, and particular renal failure. In vivo and in vitro studies indicate that AGEs represent an important class of uremic toxins. This review focuses on the chemistry behind the formation of AGEs, possible mechanisms underlying the accumulation of AGEs in uremia, clinical and therapeutic implications, and possible nutritional consequences.
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PMID:Advanced glycation end products in uremia. 1468 61

Diabetic nephropathy affects 30-40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product epsilon(gamma-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mm glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM epsilon(gamma-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated epsilon(gamma-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor beta1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor beta1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.
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PMID:Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells. 1532 85

Cystinuria is a common inherited amino-aciduria resulting in abnormal urinary excretion of cystine and the dibasic aminoacids, lysine, arginine and ornithine. Formation of cystine kidney stones, recurrent infections and subsequent renal failure are the main complications of the disease. Recently, the gene SLC3A1 and SLC7A9, encoding the two subunits rBAT et b0,+AT of the proximal renal transporter complex, have been identified. In this article, we report the medical history of a 30-year-old patient and discuss the recent molecular progress, the clinical evolution, and the medical treatment of the cystinuria.
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PMID:[Cysteine lithiasis]. 1549 70


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