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)

Induction of interleukin 1 activates vascular endothelial and kidney mesangial cells, and increases production of type IV (basement membrane) collagen. Hence, genes within the interleukin 1 gene cluster are potential candidates in the pathogenesis of diabetic nephropathy. In a previously validated case-control study from Northern Ireland, consisting of 95 patients with insulin-dependent (type 1) diabetes and nephropathy (cases) and 96 patients with insulin-dependent (type 1) diabetes without nephropathy (controls), the authors performed PCR-based genotyping of specific DNA polymorphisms within the interleukin 1A, interleukin 1B, interleukin 1 (type 1) receptor and interleukin 1 receptor antagonist genes. The groups were matched for age at onset and duration of diabetes. A statistically significant increase was found in the allele frequency of the interleukin 1B*2 allele in cases compared to controls (chi2=7. 19, df.=1; P=0.007, Pcorr=0.028). The results of this study suggest that the interleukin 1B*2 allele, or a susceptibility factor in linkage disequilibrium with this allele, is associated with diabetic nephropathy in the Northern Ireland population.
Cytokine 1998 Dec
PMID:An interluekin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy. 1004 23

Diabetic nephropathy is the leading cause of end-stage renal disease in the United States and is a major contributing cause of morbidity and mortality in patients with diabetes. Despite conventional therapy to improve glycemic and blood pressure control the incidence of diabetic nephropathy is reaching epidemic proportions worldwide. As the major pathologic feature of diabetic nephropathy is diffuse mesangial matrix expansion, the pro-sclerotic cytokine transforming growth factor-beta, TGF-beta, is a leading candidate to mediate the progression of the disease. Numerous studies have now demonstrated that TGF-beta is a key factor in experimental models of diabetic kidney disease as well as in patients with diabetic nephropathy. Recent studies have begun to explore the mechanisms by which TGF-beta is stimulated by high glucose and how TGF-beta exerts its matrix-stimulating effects on renal cells. TGF-beta may also be involved in mediating the vascular dysfunction of diabetic kidney disease via its effects on the key intracellular calcium channel, the inositol trisphosphate receptor (IP(3)R). As there is substantial evidence for a cause and effect relationship between upregulation of TGF-beta and the progression of diabetic kidney disease, future studies will seek to establish specific targets along these pathways at which to intervene.
Cytokine Growth Factor Rev
PMID:TGF-beta in diabetic kidney disease: role of novel signaling pathways. 1070 59

The role of inflammatory cytokines in the pathogenesis of diabetic nephropathy has been studied in streptozotocin-induced diabetic rats. Rat kidneys were examined by light and electron microscopy and kidney homogenates were also analyzed by Western blot and flow cytometry for the expression of markers of inflammation namely, CD4+ and CD8+ T cells, macrophages, MHC classes I and II, the proinflammatory cytokines tumor necrosis factor-alpha, interferon-gamma and nitric oxide (NO). Light and electron microscope examination revealed infiltration of mononuclear cells throughout the renal parenchyma, with the glomeruli being more severely affected especially at 8 months after disease induction. Western blot and flow cytometric analyses revealed the infiltrating cells to be CD4+ T cells, CD8+ T cells and macrophages. Western blot analyses also revealed increased expression of the proinflammatory and Th1 cytokines tumor necrosis factor-alpha, interferon-gamma as well as nitric oxide. Using flow cytometry, we have shown that the difference in expression of CD4+ T cells in control and diabetic kidneys is more significant at 1 month than at 8 months, while expression of CD8+ T cells is more significant at 8 months. We speculate therefore that diabetic nephropathy is probably initiated and driven by a Th1 process. CD8+ T cells, however, become more significant at later stages of the disease when tissue loss is evident. Since NO induction also occurs only after 8 months, we hypothesize that NO might be significant for the later stages of the disease. Our data implicate inflammation in the pathogenesis of diabetic nephropathy in view of the overexpression of the proinflammatory cytokines TNF-alpha and IFN-gamma and the cells that secrete them in the early and late phases of the disease.
Cytokine 2005 Aug 07
PMID:Streptozotocin-induced diabetic nephropathy in rats: the role of inflammatory cytokines. 1597 18

Diabetes mellitus and its complications are a public health problem. Diabetic nephropathy has become the main cause of renal failure, and furthermore is associated with a dramatic increase in cardiovascular risk. Unfortunately, the mechanisms leading to the development and progression of renal injury in diabetes are not yet fully known. There is now evidence that activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Furthermore, different inflammatory molecules, including pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), play a critical role in the development of microvascular diabetic complications, including nephropathy. This review discusses the role of TNF-alpha as a pathogenic factor in renal injury, focusing on diabetic nephropathy, and describes potential treatment strategies based on modulation of TNF-alpha activity.
Cytokine Growth Factor Rev 2006 Dec
PMID:The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. 1711 15

End-stage renal disease (ESRD) involves an inflammatory process. Interleukin-1 receptor antagonist (IL-1Ra) and interleukin-1beta gene polymorphisms affect susceptibility to the disease in several inflammatory diseases. We investigated whether these polymorphisms are involved in ESRD by genotyping DNA from 602 dialyzed patients and 433 controls with polymerase chain reaction and digestion with restriction endonuclease. Allele 2 of the IL-1Ra VNTR polymorphism was associated with ESRD (OR=1.46, 95% CI 1.19-1.78). We also found a strong association between this allele and recurrent peritonitis in peritoneal dialysis patients. Odds ratio for the risk allele was higher compared to entire ESRD group (OR=3.6, 95% CI 1.70-7.44). The homozygosity for the allele 2 was associated with disease progression, especially in patients with diabetic nephropathy and glomerulonephritis. For the patients from these two subgroups having 2.2 genotype, the mean time from disease onset to ESRD was 1.5 and 2.2 years, respectively, compared to 6.4 and 9.8 years for those with 1.1 genotype. The IL-1Ra allele 2 is associated with ESRD in our dialyzed patients. Our results demonstrate for the first time the association of the IL-1Ra allele 2 with faster progression to ESRD. If confirmed in other populations, it might be a predictor of faster disease progression.
Cytokine 2006 Nov
PMID:Interleukin-1 receptor antagonist gene polymorphism affects the progression of chronic renal failure. 1722 77

Conventional therapies for diabetic mellitus are not effective in preventing the progression from early diabetic nephropathy (DN) to end-stage renal disease. The role of inflammation in the pathogenesis of DN has been implicated both clinically and experimentally, which provides an alternative therapeutic target for DN. Anti-inflammatory impact of mycophenolate mofetil (MMF) alone and in combination with insulin had been observed in a rat model of experimental DN. In this study, the diabetic rats were subjected to different treatments. Compared to control, the expression levels of CD68, NGF, and NF-kappaB p65, as determined immunohistochemically, were elevated in diabetic rats. Treatment with combined MMF/insulin is associated with a significant reduction in renal tissue of NGF and NF-kappaB p65 expression, macrophage infiltration. It also partially improved the renal function and attenuated renal hypertrophy at early stage of DN. CD68 was found to positively correlate with urinary albumin excretion and NGF. The combined use of MMF/insulin seemed to offer more protections in rats with experimental diabetic renal injury, and the protective effects of MMF might be due to its anti-inflammatory actions through inhibition of NF-kappaB activation and reduction of T cells and macrophage infiltration and/or other kidney chemokine productions.
Cytokine 2006 Dec
PMID:Combined MMF and insulin therapy prevents renal injury in experimental diabetic rats. 1733 3

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.
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PMID:Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. 1742 53

Several works in the setting of early experimental diabetic nephropathy using anti-inflammatory drugs, such as mycophenolate mofetil (MMF), have shown that prevention of the development or amelioration of renal injury including proteinuria. The exact mechanisms by which anti-inflammatory drugs lower the albuminuria have no still to clarify well. In this study, diabetes was induced by injection of streptozotocin after uninephrectomy. Rats were randomly divided into three groups: control group, diabetic group and diabetic group treated with MMF. Elevated 24h urinary albumin excretion rate was markedly attenuated by MMF treatment. In diabetic rats receiving no treatment, there were increase in ED-1+ cells in the glomeruli, which were effectively suppressed by MMF treatment. The expression of nephrin and podocin protein was reduced in the glomeruli from diabetic rats, and MMF treatment significantly increased the expression of nephrin and podocin. The expression of IL-1, TNF-alpha and 3-NT protein in the glomeruli were significantly increased in diabetic rats, which were all significantly inhibited by MMF treatment. Our results show that MMF could decrease urinary albumin excretion, which mechanism may be at least partly correlated with upregulated expression of nephrin and podocin in the glomeruli of diabetic rat.
Cytokine 2008 Oct
PMID:Nephrin and podocin loss is prevented by mycophenolate mofetil in early experimental diabetic nephropathy. 1872 82

Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-alpha (TNF-alpha). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-alpha inhibition with the use of soluble TNF-alpha receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-alpha might be an efficacious treatment for renal disease secondary to diabetes mellitus.
Cytokine Growth Factor Rev 2009 Apr
PMID:Tumor necrosis factor-alpha as a therapeutic target for diabetic nephropathy. 1925 67

Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p<0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p<0.01 and p<0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R=0.49, p<0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R=0.61, p<0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease.
Cytokine 2009 Jul
PMID:Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy. 1940 9


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