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: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C viral infection occurs relatively low in Korea compared to hepatitis B. However, it progresses into chronic hepatitis and cirrhosis more frequently than HBV. It may be associated with cryoglobulinemia and glomerulonephritis, both in native and transplanted kidneys. We report three cases of membrano-proliferative glomerulonephritis type I in anti-HCV positive, but cryoglobulin-negative patients, presenting massive proteinuria, two in native kidneys and one in an allograft. HCV-RNA was positive in sera of two patients. Two were cirrhotic and ALT was mildly elevated in two. In addition to the characteristic membranoproliferative feature, two native kidneys overlapped with features of diabetic nephropathy. Immunofluorescence demonstrated mainly IgM and C3 deposits along the peripheral capillary walls. Subendothelial electron dense deposits were present in the glomeruli of all three cases with subepithelial and intramembranous deposits in two. HCV-RNA was associated not only with a greater amount of immune deposits but also with subepithelial and intramembranous deposits, indicating the role of active infection.
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PMID:Membranoproliferative glomerulonephritis associated with HCV infection in native kidneys and renal allograft. 988 79

Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.
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PMID:Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). 1174 69

The severe diabetic nephropathy that develops in the hypertensive transgenic (mRen-2)27 rat with streptozotocin (STZ) diabetes has previously been considered angiotensin II-dependent. Because metabolic pathways are also activated in the diabetic kidney, the present study aimed to determine whether renoprotection could be afforded with inhibitors of advanced glycation end products (AGEs), ALT-946, and aminoguanidine (AG). At 6 weeks of age, nondiabetic control and STZ diabetic Ren-2 rats were randomized to receive vehicle, ALT-946 (1 g/l), or AG (1 g/l) and were studied for 12 weeks. Systolic blood pressure was unchanged with diabetes, ALT-946, or AG. Both kidney weight and glomerular filtration rate were increased with diabetes and unchanged with ALT-946 or AG. ALT-946 and AG equally ameliorated glomerulosclerosis and medullary pathology; however, ALT-946 did reduce cortical tubular degeneration to a greater extent than AG. Albumin excretion rate, which was elevated with diabetes, was reduced with ALT-946 but not AG. AGE immunolabeling was increased in glomeruli and reduced with ALT-946 and AG. These findings indicate that even in the context of renal injury presumed to be primarily blood pressure- and/or angiotensin II-dependent, approaches that interfere with metabolic pathways such as inhibitors of AGE formation can confer renal protection in experimental diabetes.
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PMID:ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. 1240 20

The annual statistical survey conducted at the end of 2000 by the Japanese Society for Dialysis Therapy collected responses from 3358 (99.94%) of 3360 institutions. Japan's total dialysis patient population at the end of the year 2000, as identified by this survey, was 206,134, an increase of 8921 (4.5%) over 1999. This translates to 1624.1 patients per million population. The annual crude mortality rate was 9.4% for the period starting at the end of the year 1999 and ending at the end of the year 2000. The mean patient age at the initiation of dialysis treatment was 63.8 (+/- 13.9; +/- SD) years; the mean age of the overall dialysis patient population was 61.2 years (+/- 13.3). Both these mean ages, which had been increasing since 1983, again continued to increase. Among the primary diagnosis, the prevalence of diabetic nephropathy had continued to increase again since 1999, to 36.6%, whereas that of chronic glomerulonephritis had continued to decline, down to 32.5%, during the same one-year period since the 1999 survey. The 2000 years-end survey incorporated the following additional variables for the first time: usage of oral antihypertensives, pre- and post-dialysis systolic and diastolic blood pressures, serum HDL cholesterol level, types and dosage of oral Vitamin D analogs administered, dosage of oral calcium carbonate administered, history of intervention for peripheral vascular disease (bypass surgery, synthetic graft replacement, stenting), history of coronary artery bypass grafting (CABG), history of percutaneous transluminal coronary angioplasty (PTCA), whether stenting had been previously performed for the treatment of ischemic heart disease, number of cigarettes smoked, the type of vascular access used at the initiation of dialysis, and the year and month the vascular access was created. The survey results indicate that 60.9% of the total dialysis patient population was using oral antihypertensives. The patients' mean serum HDL cholesterol level was 47.65 +/- 18.47 mg/dL, showing positive correlation with serum albumin level and reverse correlation with body mass index. 1.6% of all dialysis patients had previously undergone amputation, and 0.7% had a history of bypass surgery for peripheral vascular disorder. 4.5% of hemodialysis patients had a history of cardiac infarction, 1.6% had previously undergone CABG, and 2.8%, PTCA. At the time the survey was conducted, 2.0% of all dialysis patients were undergoing oral Vitamin D analog pulse therapy, and 6% were undergoing intravenous Vitamin D analog pulse therapy. A history of amputation, myocardial infarction, cerebral infarction, and cerebral bleeding were identified as high-risk factors of vital prognosis. Additionally, high mortality risk was associated with the following: glutamic-pyruvic transaminase levels exceeding 20 IU/L; positive HCV antibody status; comorbid conditions such as hepatic cell carcinoma and liver cirrhosis; platelet counts below 100,000/mL or equal to or greater than 200,000/mL; C-reactive protein levels of 0.2 mg/dL and higher, leukocyte counts of less than 3000/mL or equal to or greater than 8000/mL; and body mass index of below 22 kg/m2, as well as total serum cholesterol levels of below 160 mg/dL or equal to or greater than 260 mg/dL.
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PMID:The current state of chronic dialysis treatment in Japan (as of December 31, 2000). 1292 Nov 11

Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
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PMID:The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. 1295 2

Advanced glycation endproducts (AGEs) have been postulated to play a role in the development of both nephropathy and large vessel disease in diabetes. However, it is still not clear which AGE subtypes play a pathogenetic role and which of several AGE receptors mediate AGE effects on cells. This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy. It also demonstrates similar effects of aminoguanidine and ramipril (an angiotensin converting enzyme inhibitor) on fluorescent and immunoassayable AGE levels, renal protein kinase C activity, nitrotyrosine expression, lysosomal function, and protein handling in experimental diabetes. These findings indicate that inhibition of the renin angiotensin system blocks both upstream and downstream pathways leading to tissue injury. We postulate that the chemical pathways leading to advanced glycation endproduct formation and the renin angiotensin systems may interact through the generation of free radicals, induced both by glucose and angiotensin II. There is also evidence to suggest that AGE-dependent pathways may play a role in the development of tubulointerstitial fibrosis in the diabetic kidney. This effect is mediated through RAGE and is TGF-beta and CTGF-dependent.
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PMID:Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease. 1456 9

Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a role in the development and progression of diabetic nephropathy. Furthermore, there is increasing evidence that advanced glycation end products (AGE) play an important role in diabetic renal disease. The objectives of this study were first to characterize renal injury in diabetic apolipoprotein E knockout (apo E-KO) mice and second to explore the role of AGE in the development and progression of renal disease in this model. Diabetes was induced by injection of streptozotocin in 6-wk-old apo E-KO mice. Diabetic animals received no treatment or treatment with the inhibitor of AGE formation aminoguanidine (1 g/kg per d) or the cross-link breaker [4,5-dimethyl-3-(2-oxo2-phenylethyl)-thiazolium chloride] ALT-711, which cleaves preformed AGE (20 mg/kg per d) for 20 wk. Nondiabetic apo E-KO mice as well as nondiabetic and diabetic C57BL/6 mice served as controls. Compared with nondiabetic apo E-KO mice, induction of diabetes in apo E-KO mice resulted in accelerated renal injury characterized by albuminuria and glomerular and tubulointerstitial injury. These abnormalities were associated with increased expression of collagen type I and type IV and transforming growth factor-beta1 (TGF-beta1), increased alpha-smooth muscle actin immunostaining and macrophage infiltration, and increased serum and renal AGE. The two treatments, which attenuated renal AGE accumulation in a disparate manner, were associated with less albuminuria, structural injury, macrophage infiltration, TGF-beta1, and collagen expression. The accelerated renal injury that was observed in diabetic apo E-KO mice was attenuated by approaches that inhibit renal AGE accumulation.
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PMID:Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products. 1528 98

This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-alpha as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-alpha. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711.
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PMID:Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. 1550 73

Epidemiological studies have implicated hepatitis C virus (HCV) infection in the pathogenesis of diabetes mellitus (DM) both in the population as a whole and after solid organ transplantation. Whether this association exists in patients with end-stage renal disease (ESRD) undergoing dialysis is unclear. The aim of this study is to investigate the relationship between HCV and DM in a large group (n=742) of patients with ESRD from Europe and North America. The presence of diabetes was ascertained by using American Diabetes Association guidelines based on fasting glucose measurement and medication history. Presence of HCV infection was assessed by serum testing for anti-HCV antibodies. The prevalence of anti-HCV antibody positive patients was 15% (112/742); the frequency of DM was higher among anti-HCV positive than -HCV negative patients but the difference did not approach statistical significance, 32% (36/112) vs 29.5% (186/630). The frequency of patients with diabetic nephropathy was not higher in anti-HCV positive than -negative patients; 21.4% (24/112) vs 23.3% (147/630), NS. Logistic regression model showed an independent and significant link between anti-HCV seropositive status and raised GPT (P=0.032), male gender (P = 0.0462), positive history of prior renal transplant (P=0.0006), and longer time on dialysis (P=0.00001). In summary, no link between anti-HCV antibody and DM occurred in this ESRD population; there was no association between rate of anti-HCV antibody and diabetic nephropathy.
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PMID:Hepatitis C virus infection and diabetes mellitus in end-stage renal disease: evidence of a negative association. 1687 74

Hepatitis C virus (HCV) infection is often associated with kidney diseases such as membranoproliferative glomerulonephritis (MPGN), with and without cryoglobulinemia, membranous glomerulonephritis (MGN) or glomerulosclerosis (FSGN). The aim of our study was to determine the frequency of HCV with or without hypertransaminasemia in patients with chronic nephropathy in the predialytic phase. We tested 340 subjects with chronic renal insufficiency (CRI) from our hospital's nephrology outpatient clinic for anti-HCV antibodies. In positive subjects we tested for HCV RNA by PCR method, monitoring, for at least 4 months, common biohumoral parameters including transaminases (AST, ALT). Of the 340 subjects, 46 (13.5%) were positive for HCV RNA, and 8 of these (17%) showed constant alteration of transaminases. HBsAg was found in 8 of the total study population (2.3%), and none of these showed altered transaminases. Type II diabetes mellitus was found in 26% (12/46) of the HCV-RNA positive patients, and in only 12.5% (37/294) of the negative ones. The kidney diseases we found in the 46 HCV-RNA positive patients were: diabetic nephropathy in 11 (23.9%), MPGN in 7 (15.2%), MPGN + cryoglobulinemia in 2 (4.3%), interstitial nephropathy in 4 (8.7%), IgA mesangial GN in 3 (6.5%), hypertensive nephropathy in 2 (4.3%), focal and segmental GN in 1 (2.2%), urologic disease in 4 (8.7%), other (hematological, genetic, iatrogenic) in 3 (6.6%), unknown in 9 (19.6%). Our data show that the most frequent kidney diseases associated with HCV infection were diabetic related nephropathy and MPGN with and without cryoglobulinemia. HCV infection had a positive association with diabetes. It is interesting to note that in this study population the hepatitis C concomitant to kidney disease was unusually mild: only 4 of the 46 subjects (9%) showed clinical, biohumoral and ultrasound evidence of cirrhosis.
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PMID:Hepatitis C and kidney disease. 1793 31


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