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)

The elevated glomerular filtration rate that occurs in 25 to 40 percent of insulin-dependent diabetics has been proposed as having a role in the initiation and evolution of diabetic nephropathy. We report that both enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells and increased expression of IGF-1 receptor can cause glomerular hyperfiltration, and that upregulated expression of ICAM-1 can promote the intraglomerular infiltration of mononuclear cells, which were prevented by aldose reductase inhibitor. The results of United Kingdom Prospective Diabetes Study (UKPDS) will also be discussed.
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PMID:[Diabetic nephropathy--recent advances in its mechanism and treatment]. 1019 39

We recently demonstrated that induction of adhesion molecules is tissue, cell type, and blood vessel size specific. We examined here whether the glomeruli, a peculiar vascular system, express adhesion molecules in a specific manner in the murine kidney. In addition, since serum levels of soluble adhesion molecules have been reported to be elevated in diabetic patients, we examined the influence of diabetes mellitus on the induction of adhesion molecules in the kidney. Analysis of E-selectin mRNA expression by in situ hybridization indicated that it was selectively induced in glomeruli by intravenous administration of interleukin-1beta, while ICAM-1 mRNA expression was seen diffusely in endothelium lining the small arteries and capillaries or in glomeruli, and VCAM-1 mRNA expression was most prominent in endothelial cells of larger blood vessels. Induction of E-selectin mRNA expression in glomeruli by proinflammatory stimuli was augmented in streptozotocin-induced diabetic mice as compared with control mice, while ICAM-1 or VCAM-1 mRNA induction was only slightly influenced. Furthermore, immunohistochemical analysis showed that selective expression of E-selectin in glomeruli was augmented predominantly in epithelial cells, depending on the duration of diabetes mellitus, in KK-Ay mice. These findings suggest that glomerulus-specific expression of E-selectin is related to the development of diabetic nephropathy.
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PMID:Tissue-specific induction of E-selectin in glomeruli is augmented following diabetes mellitus. 1154 98

Reflux nephropathy (RN) is a major cause of end-stage renal failure in children and young adults. Intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein, has a role in the regulation of interaction among immune cells. It has been demonstrated that increased levels of tubular ICAM-1 correlate with an extent of tubular damage in diabetic nephropathy. We hypothesized that ICAM-1 local synthesis is altered in reflux nephropathy and therefore designated this study to investigate ICAM-1 expression in RN. The kidney specimens from six patients with severe reflux nephropathy secondary to primary vesicoureteral reflux were obtained at the time of nephrectomy. Control materials included normal kidney specimens obtained from three adult patients during partial nephrectomy for an incidentaloma. Fluorescent immunohistochemistry was carried out using monoclonal antibodies to ICAM-1 utilizing confocal laser scanning microscopy. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of ICAM-1. In the control kidneys, there was lack of ICAM-1 immunoreactivity in the interstitium and proximal tubules and moderate immunoreactivity in the glomerulus. In the refluxing kidney there was strong ICAM-1 immunoreactivity in the glomerulus, interstitium and proximal tubules. The RT-PCR showed strong ICAM-1 mRNA expression in the refluxing kidneys and absent or weak ICAM-1 expression in the controls. Our findings of increased expression of ICAM-1 in the severe reflux nephropathy kidney suggests that ICAM-1 may play a role in the pathogenesis of renal parenchymal damage associated with RN.
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PMID:ICAM-1 expression is upregulated in reflux nephropathy. 1275 65

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.
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PMID:Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. 1451 44

Diabetic nephropathy is a leading cause of end-stage renal failure and is a growing concern given the increasing incidence of type 2 diabetes. Diabetic nephropathy is associated with progressive kidney macrophage accumulation and experimental studies suggest that intercellular adhesion molecule (ICAM)-1 facilitates kidney macrophage recruitment during type 1 diabetes. To ascertain the importance of ICAM-1 in promoting type 2 diabetic nephropathy, the development of renal injury in ICAM-1 intact and deficient db/db mice with equivalent hyperglycemia and obesity between ages 2 and 8 mo was examined and compared with results with normal db/+ mice. Increases in albuminuria (11-fold), glomerular leukocytes (10-fold), and interstitial leukocytes (three-fold) consisting of predominantly CD68+ macrophages were identified at 8 mo in diabetic db/db mice compared with nondiabetic db/+ mice. In comparison to db/db mice, ICAM-1-deficient db/db mice had marked reductions in albuminuria at 6 mo (77% downward arrow) and 8 mo (85% downward arrow). There was also a significant decrease in glomerular (63% downward arrow) and interstitial (83% downward arrow) leukocytes in ICAM-1-deficient db/db mice, which were associated with reduced glomerular hypertrophy and hypercellularity and tubular damage. The development of renal fibrosis (expression of TGF-beta1, collagen IV, and interstitial alpha-smooth muscle actin) was also strikingly attenuated in the ICAM-1-deficient db/db mice. Additional in vitro studies showed that macrophage activation by high glucose or advanced glycation end products could promote ICAM-1 expression on tubular cells and macrophage production of active TGF-beta1. Thus, ICAM-1 appears to be a critical promoter of nephropathy in mouse type 2 diabetes by facilitating kidney macrophage recruitment.
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PMID:Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. 1587 83

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-beta, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-kappaB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-gamma was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-kappaB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB. However, pioglitazone did not show the changes in the presence of PPAR-gamma antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-kappaB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.
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PMID:Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation. 1719 Sep 10

In PTC, it is clear that TGF-beta1 synthesis may be controlled independently at the levels of transcription and translation. In the context of diabetic nephropathy glucose is a potent stimulus of TGF-beta1 promoter activity. The resultant transcript is however poorly translated such that stimulation of PTC with glucose does not increase de novo TGF-beta1 protein synthesis. Although diabetes is a "metabolic" disease, in the kidney, nephropathy is associated with an inflammatory cell infiltrate. For example using the GK rat model of type II diabetes, we have demonstrated that progressive renal disease is associated with a prominent macrophage influx. This led us to examine TGF-beta1 regulation when the effects of macrophage derived cytokines such as platelet derived growth factor and interleukin-1 are combined with exposure to elevated glucose concentrations. These studies have demonstrated that such cytokines specifically facilitate translation of glucose induced TGF-beta1 transcripts. In addition, direct interaction between monocyte-macrophage CD18 and PTC cell surface ICAM-1 stimulates TGF-beta1 synthesis. Recent data from numerous experimental systems have suggested that the extracellular matrix component hyaluronan (HA) may be involved in the regulation of the inflammatory process. We have now identified HA based structures synthesised on the surface of PTC, which act to prevent PTC-macrophage interaction through ICAM-1 thus preventing macrophage driven TGF-beta1 synthesis. Disease promoting cytokines such as IL-1beta down-regulate these structures whilst potential therapeutic agents such as BMP-7 increase their assembly, that HA may possess disease limiting activity.
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PMID:The role of proximal tubular cells in interstitial fibrosis: understanding TGF-beta1. 1747 23

Previously, we have reported that pigment epithelium-derived factor (PEDF) ameliorates albuminuria and inhibits matrix protein deposition in the kidney of streptozotocin (STZ)-induced diabetic rats, suggesting a renoprotective effect of PEDF in early stages of diabetic nephropathy. As inflammation is a major contributor to the development and progression of diabetic nephropathy, we examined in the present study whether PEDF inhibits renal inflammation in diabetic kidney. Diabetic rats received an intravenous injection of an adenovirus expressing PEDF (Ad-PEDF) or the same titer of a control virus. Three wk after the injection, diabetic rats treated with the control virus showed significantly elevated renal levels of proinflammatory factors such as ICAM-1, MCP-1, TNF-alpha, and VEGF compared with age-matched nondiabetic controls. Ad-PEDF effectively suppressed the overexpression of these proinflammatory factors in diabetic kidneys. In cultured primary human renal mesangial cells (HMC), the high-glucose medium-induced upregulation of VEGF and MCP-1 was largely blocked by PEDF. Furthermore, PEDF inhibited high glucose-induced activation of NF-kappaB, a key transcription factor mediating inflammatory responses, and hypoxia-inducible factor-1, a major activator of VEGF expression in HMC. These results suggest that the renoprotective effect of PEDF against diabetic nephropathy may be partially through its anti-inflammatory activity, likely by blocking the NF-kappaB and HIF-1 pathways.
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PMID:Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy. 1832 21

Hyperuricemia has recently been recognized to be a risk factor for nephropathy in the diabetic subject. We tested the hypothesis that lowering uric acid with a xanthine oxidase inhibitor might reduce renal injury in the diabetic mouse. Diabetic (db/db) mice were treated with allopurinol or no treatment for 8 wk. Serum uric acid, renal function, and histology were assessed at death. The direct effect of uric acid in human proximal tubular epithelial cells was also evaluated under normal or high glucose condition. We found that db/db mice developed hyperuricemia, albuminuria, mesangial matrix expansion, and mild tubulointerstitial disease. Allopurinol treatment significantly lowered uric acid levels, reduced albuminuria, and ameliorated tubulointerstitial injury, but it did not prevent mesangial expansion. The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells. Interestingly, allopurinol did not reduce oxidative stress in the kidney. An inflammatory role of uric acid on tubular cells was also confirmed by our in vitro evidence that uric acid directly induced ICAM-1 expression in the human proximal tubular cell. In conclusion, hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice. Lowering uric acid may reduce tubulointerstitial injury in diabetes.
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PMID:Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. 1945 27

Chronic inflammation and increased oxidative stress (OS) play an important role in diabetic nephropathy progression. Herein, we show that mesangial cells from streptozotocin-induced aging diabetic mice, a model of progressive diabetic nephropathy, exhibited increased OS and a proinflammatory phenotype characterized by elevated chemokines and ICAM-1 expression. This phenotypic change was consistent with the extensive inflammatory lesions present in aging diabetic kidneys and was not found in mesangial cells from old and young controls or young diabetic mice. Activation of the c-Jun NH(2)-terminal kinase (JNK) pathway was a likely contributor to the proinflammatory phenotype of aging diabetic mesangial cells since 1) phosphorylated JNK levels and JNK kinase activity were increased in these cells, 2) suppression of JNK significantly decreased monocyte chemoattractant protein-1 (MCP-1) production in these cells, and 3) activation of JNK in normal mesangial cells induced inflammation. Elevated OS in aging diabetic mesangial cells may be a cause of JNK activation and inflammation, because antioxidant treatment decreased JNK phosphorylation and MCP-1 production. Additionally, decreased expression of mitogen-activated protein kinase phosphatase 5 (MKP5) may also contribute to increased JNK and inflammation in aging diabetic mesangial cells since overexpression of MKP5 in these cells normalized phosphorylated JNK levels and reversed the proinflammatory phenotype. Moreover, knocking down of MKP5 expression in old control mesangial cells resulted in JNK activation and MCP-1 production, a phenotype seen in aging diabetic mesangial cells. Interestingly, MKP5 phosphatase activity was diminished by free radicals in vitro. Thus, OS may induce inflammation in mesangial cells by activating JNK through either a direct activation of JNK or indirectly by suppression of MKP5 activity. Proinflammatory phenotype of mesangial cells may contribute to chronic inflammatory lesions and disease progression of aging diabetic mice.
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PMID:Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells. 1977 74


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