Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive renal vascular sclerosis is a key feature of chronic kidney disease (CKD). Adiponectin, an adipokine with potent anti-inflammatory and antiatherosclerotic properties, is associated with insulin resistance, type II diabetes and cardiovascular disease. In this study, we evaluated the predictive value of adiponectin for the progression of CKD in patients enrolled in the Mild to Moderate Kidney Disease Study. The primary end point was defined as a doubling of the baseline serum creatinine and/or terminal renal failure in 177 patients who completed a prospective follow-up of 7 years. Patients who reached a progression endpoint (n=65) were significantly older, had higher baseline serum creatinine, proteinuria and adiponectin concentrations and more components of the metabolic syndrome. A gender-stratified Cox model revealed adiponectin in men as a significant predictor of progression after adjustment for age, glomerular filtration rate, and proteinuria. Male patients with adiponectin levels above their ROC analysis-derived optimal cutoff of 4 microg/ml had a significantly faster progression than patients below this point. This prospective long-term study in patients with CKD indicates high adiponectin as a novel independent predictor of disease progression in men but not in women. Our observation may be relevant for other conditions of progressive vascular sclerosis and diabetic nephropathy.
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PMID:Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: the Mild to Moderate Kidney Disease Study. 1755 49

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPARalpha and -gamma are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPARalpha/gamma dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-beta1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPARalpha and -gamma were expressed, tesaglitazar treatment abolished high glucose-induced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPARalpha/gamma agonists in treating type 2 diabetes and diabetic nephropathy.
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PMID:Peroxisome proliferator activated receptor alpha/gamma dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice. 1753 62

Hypertension is caused by metabolic syndrome. The primary cause of hypertension, however, is excess salt intake and an impaired renal salt excretory mechanism of the tubuloglomerular feedback mechanism involved in macula densa. Salt-losing nephropathy such as Gitelman's syndrome (which is caused by loss of function mutation in the tyhiazide-sensitive Na-Cl transporter, NCCT gene) is lacking in hypertension and has fewer cardiovascular complications despite the presence of the stimulated rennin-angiotensin-aldosterone system. It has been reported that an NCCT gene mutation is closely associated with diabetic nephropathy, suggesting an important role of NaCl metabolism in diabetic nephropathy. Loss of function of peroxisome proliferator-activated receptor(PPAR) -gamma(one of the key molecules of insulin resistance) has been shown to lead to obesity, diabetes and hypertension, suggesting a common basic background of such diseases. High insulin levels observed in insulin resistance would stimulate salt reabsorption in renal tubules, which may result in high blood pressure. Adipocytokines such as adiponectin, leptin and angiotensinogen may play some roles in metabolic syndrome. Taken together, good understanding of salt intake and its related factors in renal salt metabolism involved in metabolic syndrome will suppress further progression of atherosclerotic changes including chronic kidney disease.
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PMID:[Hypertension and metabolic syndrome/lifestyle diseases]. 1759 91

Decorin, a proteoglycan that inhibits active transforming growth factor-beta, is increased in diabetic nephropathy; however, its functional significance is unclear. In this study, we used low-dose streptozotocin to induce type 1 diabetes in wild-type (C57BL/6J Dcn(+/+)), Dcn(-/-), and Dcn(+/-) mice and studied the mice for up to 1 year of diabetes. Decorin gene dose had no effect on severity of diabetes; however, the Dcn(-/-) diabetic mice died significantly earlier than nondiabetic controls (57 versus 7.3% mortality). In contrast to wild-type diabetic mice, which failed to develop significant nephropathy, the Dcn(-/-) diabetic mice developed a significant increase in albuminuria and plasma creatinine and a concurrent decrease in circulating adiponectin levels. Interestingly, adiponectin levels at 6 months of diabetes were predictive of mortality in diabetic mice. Dcn(-/-) diabetic mice exhibited advanced glomerular lesions, including diffuse mesangial matrix accumulation and fibrin cap formation. By immunohistochemistry, Dcn(-/-) diabetic mice exhibited significant increases in glomerular transforming growth factor-beta, type I collagen, macrophage infiltration, and Nox4. We conclude that decorin is a natural protective factor against diabetic nephropathy and that the Dcn(-/-) diabetic mouse is a useful new model of progressive diabetic nephropathy.
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PMID:Decorin deficiency enhances progressive nephropathy in diabetic mice. 1788 68

Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.
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PMID:Genetic factors in diabetic nephropathy. 1794 68

Diabetic nephropathies are characterized by glycogen accumulation in distal tubular cells, which eventually leads to their apoptosis. The present study aims to determine whether adiponectin and AMPK are involved in the regulation of glycogen synthase (GS) in these structures. Western blots of isolated distal tubules revealed the presence of adiponectin receptor ADIPOR1, catalytic AMPK subunits alpha(1) and alpha(2), their phosphorylated active forms, and the glycogen-binding AMPK subunit beta(2). ADIPOR2 was not detected. Expression levels of ADIPOR1, AMPKalpha(1), AMPKalpha(2), and AMPKbeta(2) were increased in streptozotocin-treated diabetic rats, whereas phosphorylated active AMPK levels were strongly decreased. Immunohistochemistry revealed the presence of ADIPOR1 on the luminal portion of distal tubules and thick ascending limb cells. Catalytic subunits alpha(1) and alpha(2), their phosphorylated active forms, and the glycogen-binding subunit beta(2) were also found in the same cells, confirming immunoblot results. In vitro, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR; 2 mM) and globular adiponectin (10 mug/ml) activated catalytic AMPK in distal tubules isolated from kidneys of normal rats but much more weakly in those from diabetic rats. GS inhibition paralleled AMPK activation in both groups of animals: active GS levels were low in control animals and elevated in diabetic ones. Finally, glucose-6-phosphate, an allosteric activator of GS, was also increased in diabetic rats. These results demonstrate that in distal tubular cells, adiponectin through luminal ADIPOR1 activates AMPK, leading to the inhibition of GS. During hyperglycemia, this regulation is altered, which may explain, at least in part, the accumulation of large glycogen deposits.
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PMID:Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats. 1825 13

Adiponectin levels are increased in patients with type I diabetes especially in the presence of microangiopathy. Here we determined the predictive value of serum adiponectin levels and 8 adiponectin gene polymorphisms for mortality, cardiovascular events and end-stage renal disease in type I diabetic patients. This prospective, observational follow-up study of type I diabetics consisted of 438 patients with overt diabetic nephropathy that were compared to 440 type I patients with normal albumin excretion. These two groups were followed an average of 8 years and generally matched for gender, age and duration of diabetes. Cox regression analysis of 373 patients showed a covariate-adjusted hazard ratio for all-cause mortality of 1.46 for a change of one standard deviation in log10 of serum adiponectin. There was no association with cardiovascular events; however, serum adiponectin levels predicted end stage renal disease in a covariate-adjusted analysis. Two of eight gene polymorphisms, found in the 878 patients, were associated with increased serum adiponectin levels but none of the polymorphisms were associated with a renal or cardiovascular outcome. These studies show that high serum adiponectin levels predict mortality and progression to end stage renal disease in type I diabetic patients.
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PMID:Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type I diabetes and diabetic nephropathy. 1897 68

A calcium channel blocker (CCB), azelnidipine (AZ), is reported to inhibit oxidative stresses, particularly when administered under blockade of the renin-angiotensin system (RAS). The purpose of this study was to investigate whether AZ inhibits oxidative stresses more potently than other CCBs under blockade of RAS and exerts renoprotection in type 2 diabetic nephropathy. Subjects were hypertensive type 2 diabetics with nephropathy, taking RAS inhibitors. The patients were randomly assigned to two groups, an AZ group (n=21, 16 mg/d) and a nifedipine-CR (NF) group (n=17, 40 mg/d). The plasma levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), adiponectin and tumor necrosis factor-alpha (TNF(alpha)), the urinary excretion of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) and 8-hydroxydeoxyguanosine (8-OHdG), and the urinary albumin-to-creatinine ratios (ACR) were determined before and after 16-week treatment. Neither metabolic parameters nor blood pressure levels differed between the two groups not only at baseline but also after the treatment. However, significant decreases in MCP-1, IL-6, hsCRP, TNF(alpha), 8-epi-PGF(2alpha), 8-OHdG and ACR levels, and a significant increase in the plasma adiponectin level were detected in the AZ group, but not in the NF group. The % change in the urinary oxidative stress markers correlated with that in ACR. Our results indicate that, in hypertensive patients with diabetic nephropathy, a combination therapy of RAS inhibitors and AZ is an effective therapeutic modality for decreasing not only blood pressure but also inflammations and oxidative stresses.
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PMID:Combination therapy with renin-angiotensin system inhibitors and the calcium channel blocker azelnidipine decreases plasma inflammatory markers and urinary oxidative stress markers in patients with diabetic nephropathy. 1871 62

Low serum adiponectin is associated with a high incidence of type 2 diabetes or coronary artery disease in the general population. Paradoxically, serum adiponectin is elevated in patients with chronic kidney disease (CKD), such as overt diabetic nephropathy. The current study aimed to investigate whether anemia was independently associated with the serum level of high-molecular-weight (HMW) adiponectin in patients with type 2 diabetes. We studied 207 type 2 diabetic patients (92 women and 115 men). Anemia was defined as a hemoglobin (Hb) <13.0g/dL in men and <12.0g/dL in women according to the guidelines of the World Health Organization (WHO). Overt nephropathy (CKD) was defined as clinical proteinuria and /or estimated glomerular filtration rate (eGFR) lower than 60mL/min for more than 3 months. The diabetic patients were divided into 4 groups according to the presence or absence of anemia and/or CKD. Serum HMW adiponectin levels were measured by a sandwich enzyme-linked immunosorbent assay. In all 207 patients with type 2 diabetes, serum total and HMW adiponectin levels were correlated positively with age, the duration of diabetes, high-density lipoprotein (HDL) cholesterol, urinary albumin, and serum erythropoietin, whereas negative correlations were found with body mass index, triglyceride, eGFR, Hb, hematocrit, and high sensitivity C-reactive protein. A stepwise regression analysis demonstrated that among several significant variables, Hb had the strongest independent influence on HMW adiponectin (beta =-0.487, P < 0.001). Diabetic patients of both sexes with anemia and CKD had the highest serum levels of HMW adiponectin among the 4 groups. In conclusion, anemia is associated with marked elevation of serum HMW adiponectin levels in diabetic patients who have CKD, and this elevation is independent of renal function.
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PMID:Anemia is associated with an elevated serum level of high-molecular-weight adiponectin in patients with type 2 diabetes independently of renal dysfunction. 1976 61

Adiponectin is secreted by white adipose tissue and exists as the most abundant adipokine in the human plasma. Recent research has indicated that plasma adiponectin levels are inversely correlated with body mass index (BMI) and insulin resistance. Reduction of plasma adiponectin levels is commonly observed in the patients with type 2 diabetes (T2D) and/or in those who are obese in comparison with healthy control individuals. The adiponectin (AdipoQ) gene has a moderate linkage disequilibrium (LD), but two small LD blocks are observed, respectively, in the promoter region and the boundary of exon 2-intron 2. Genetic association studies have demonstrated that single nucleotide polymorphisms (SNPs) +45G15G(T/G) in exon 2 and +276G/T in intron 2 of the AdipoQ gene confer the risk susceptibility to the development of T2D, obesity and diabetic nephropathy (DN). The SNPs in the promoter region, including -11426A/G, -11377C/G and -11391G/A, are found to be associated with T2D and DN. Recent research has indicated that the promoter polymorphisms interfere with the AdipoQ promoter activity. The haplotypes constructed by the promoter polymorphisms and SNP +276G/T in intron 2 are associated with circulating adiponectin levels. This review summarises genetic and pathophysiological relevancies of adiponectin and discusses about the biomarkers of adiponectin plasma protein variation and genomic DNA polymorphisms.
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PMID:Biomarkers of adiponectin: plasma protein variation and genomic DNA polymorphisms. 2002 51


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