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

The field of vascular endothelial growth factor (VEGF) has recently witnessed a surge of research into its role in diabetic kidney disease. Based on its credentials as a potent inducer of vasopermeability and angiogenesis, podocyte-derived VEGF is believed to participate in the glomerular capillary hyperpermeability of macromolecules that potentially underlies the pathogenesis of diabetic albuminuria. The evidence for VEGF's role is relatively straightforward in animal models of diabetes, establishing that VEGF is upregulated in the diabetic kidney, that VEGF alone reproduces some aspects of diabetic glomerulopathy, and that antagonism of VEGF attenuates diabetic albuminuria and other associated features of the podocytopathy. However, the promise shown in the animal studies has not carried over as convincingly into the realm of human studies, as some investigators find a negative or no relationship between VEGF and diabetic nephropathy, whereas others find a positive correlation between the two. If VEGF does play a role in diabetic renal disease, its observed effects and known mechanisms seem to point squarely at the podocyte as a central target of the maladaptive VEGF overactivity.
 ...
PMID:Vascular endothelial growth factor and diabetic nephropathy. 1899 Mar 4

Diabetic nephropathy is the most serious complication in diabetes mellitus. Oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and vascular endothelial growth factor (VEGF) pathway play critical roles in the development of diabetic nephropathy. We evaluated the effects of apocynin, NADPH oxidase inhibitor on diabetic nephropathy in a type 2 diabetic rat model. Sixteen Otsuka Long Evans Tokushima Fatty (OLETF) rats and 9 Long Evans Tokushima Otsuka (LETO) were divided into the following three groups: LETO rats (n=9), control OLETF rats (n=7) and apocynin-treated OLETF rats (n=9). We examined body weights, plasma glucose levels, urinary albumin-creatinine ratio (ACR) and protein-creatinine ratio (PCR). At 50 weeks, experimental rats were sacrificed and their kidneys were extracted for hematoxylin eosin stain, immunohistochemical VEGF stain and VEGF mRNA real-time RT-PCR. To examine oxidative stress, we checked 24h urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and MDA (malondialdehyde). Urinary protein and albumin excretions were reduced after apocynin treatment, though apocynin could not significantly decrease serum glucose levels. There were improvements of glomerular and mesangial expansion in the apocynin-treated OLETF rats. Apocynin significantly decreased optical density of glomerular VEGF expression in immunohistochemical stain and reduced the concentration of 24h urinary 8-OHdG and MDA. From these results, it was suggested that apocynin may have the potential to protect against diabetic nephropathy via amelioration of oxidative stress.
 ...
PMID:Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property. 1911 63

Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.
 ...
PMID:Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. 1912 59

Recent progress with specific markers of lymphatic vessel endothelium allowed recognition of lymphangiogenic events in various disease states; however, there is little information concerning this process in human chronic renal diseases. To determine this we measured expression of the lymphatic marker D2-40 and vascular endothelial growth factor-C (VEGF-C), a major growth factor in lymphangiogenesis, in 124 human renal biopsy specimens. In the kidneys of control subjects and in uninjured areas of pathologic specimens, lymphatic vessels were detected only around the arcuate and interlobular arteries. An increase in the number of lymphatic vessels was found at the site of tubulointerstitial lesions correlating with the degree of tissue damage and more strongly correlating with areas of fibrosis than inflammation. On serial sections, lymphatic vessel proliferation was found in the tubulointerstitial area at the site of tuft adhesions to Bowman's capsule. Lymphatic growth was associated with VEGF-C expression in inflammatory mononuclear cells and tubular epithelial cells, mainly of proximal tubules. Lymphangiogenesis and VEGF-C expression was elevated in diabetic nephropathy in comparison to other renal diseases. Our results indicate that lymphangiogenesis is a common feature in the progression of the tubulointerstitial fibrosis.
 ...
PMID:Lymphatic vessels develop during tubulointerstitial fibrosis. 1933 15

There is scant knowledge on the changes in renal histological findings in type 1 diabetic patients those initially had nephrotic proteinuria and decreased renal function and later had complete remission of diabetic nephropathy by multifactorial treatment (MFT). A 44-year-old Japanese type 1 diabetic woman (duration of diabetes: 17 years) with massive proteinuria (2.9 g/day) and decreased renal function (creatinine clearance rate (Ccr): 86 mL/min) was admitted. Aggressive MFT was started with intensive insulin treatment, a low protein and low salt diet, angiotensin converting enzyme inhibitor and a diuretic. Her levels of HbA1c decreased to less than 7% within 4 months, and her high blood pressure gradually decreased and remained around mean 116/68 mmHg. Her Ccr level gradually improved and reached 108 mL/min after 78 months. Her first renal biopsy performed before MFT demonstrated diffuse and/or global accumulation of periodic acid-Schiff staining-positive mesangial matrix with increased mesangial matrix/glomerulus ratio and tubulo-interstitial fibrosis. Her second renal biopsy performed 5 years after MFT demonstrated decreased mesangial matrix/glomerulus ratio (42.0+/-4.0% to 29.2+/-1.9% [mean+/-S.D.], p<0.001) and increased her number of glomerular capillaries lumen per glomerulus (47+/-11 to 77+/-12, p<0.006). The number of vascular endothelial growth factor (VEGF)-expressing cells in the glomerular capillary significantly increased. Increased tubulo-interstitial fibrosis and the thickness of glomerular basement membrane (GBM) seen in the first biopsy specimen had decreased in the specimen taken at the second biopsy. Our case provides evidence that glomerular morphological improvements including decreased mesangial deposit and VEGF-related vasculogenesis in response to MFT goes along with functional normalization of diabetic nephropathy, which could not be attained in type 1 diabetic patients that underwent pancreas transplantation.
 ...
PMID:Complete remission of diabetic nephropathy in a type 1 diabetic patient with near-nephrotic range proteinuria and reduced renal function. 1916 60

The renal lymphatic system is cardinal in circulatory physiology and immunology. Sakamoto et al. report that lymphatic angiogenesis is increased in tubulointerstitial lesions in human chronic renal disease and correlates with tissue damage. Moreover, lymphatic growth was associated with vascular endothelial growth factor-C (VEGF-C) expression in mononuclear and tubular epithelial cells. Diabetic nephropathy had the highest level of VEGF-C and the most extensive lymphangiogenesis. The data suggest that lymphangiogenesis is a common feature in the progression of tubulointerstitial fibrosis.
 ...
PMID:The goddess of the waters. 1914 38

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and one of the leading causes of death among patients with diabetes. DN is characterized by excessive amassing of extracellular matrix with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. The high intracellular glucose environment due to an increased cellular uptake of glucose activates several pathways related to the production of advanced glycation endproducts, cytokines, chemokines, growth factors, reactive oxidative species, which are all final mediators of renal damage in human and experimental diabetes. Several growth factors have been implicated in the pathogenesis of DN, through complex intra-renal systems. Transforming growth factor beta, connective tissue growth factor, vascular endothelial growth factor, growth hormone and insulin-like growth factors are among those best known and investigated. There are also data, even though limited, on the involvement of other two growth factors, epidermal growth factor and platelet derived growth factor, in the pathogenesis of DN. These growth factors, which are generally expressed in the normal kidney and whose levels increase in relation to diabetes, have been implicated in the control of renal matrix composition, cell hypertrophy, proliferation and survival, modulation of cells of the immune system, and enzymes involved in glucose metabolism. The development of specific inhibitors of growth factors has provided further evidence for the involvement of growth factors in the development and progression of DN and further studies might help in developing new potential therapeutical interventions.
 ...
PMID:Role of growth factors in diabetic kidney disease. 1945 24

Diabetes mellitus is currently considered to be an epidemic disease. Approximately a third of individuals with type 1 and type 2 diabetes develop persistent albuminuria, lose renal function, and are at increased risk of cardiovascular and other microvascular complications. Diabetic nephropathy (DN) is the primary cause of end stage renal disease throughout the world. Microvascular dysfunction in the glomerulus appears as an early pathogenic event in progression of this renal complication. In recent years, studies with animal knockout (KO) models have revealed that uncoupling of the vascular endothelial growth factor/nitric oxide (VEGF/NO) axis leads to the glomerular alterations that characterize diabetic nephropathy. Therefore, new therapeutic alternatives may usefully target VEGF overproduction or endothelial nitric oxide availability. Recent studies also demonstrate a role for adenosine receptors in glomerular physiology and VEGF production that looks promising for therapeutic intervention of the evolution of diabetic nephropathy. However further progress is required in order to understand the dynamics of local adenosine production, in particular the extracellular metabolism of adenine nucleotides by ectoenzymes and the role of nucleoside transporters on external adenosine accumulation in the glomerulus in the pathological state. So far there is no assay that is sufficiently sensitive and accurate for subclinical diagnoses of this renal disease, which is complicated and costly to patients with often devastating effects. Current studies using proteomics offer promising alternatives for the identification of new renal injury markers. It is hoped these will permit evaluation of new therapeutic tools for more opportune intervention of this disease.
 ...
PMID:Do adenosine receptors offer new therapeutic options for diabetic nephropathy? 1948 87

The role of vascular endothelial growth factor (VEGF) in renal fibrosis, tubular cyst formation, and glomerular diseases is incompletely understood. We studied a new conditional transgenic mouse system [Pax8-rtTA/(tetO)(7)VEGF], which allows increased tubular VEGF production in adult mice. The following pathology was observed. The interstitial changes consisted of a ubiquitous proliferation of peritubular capillaries and fibroblasts, followed by deposition of matrix leading to a unique kind of fibrosis, ie, healthy tubules amid a capillary-rich dense fibrotic tissue. In tubular segments with high expression of VEGF, cysts developed that were surrounded by a dense network of peritubular capillaries. The glomerular effects consisted of a proliferative enlargement of glomerular capillaries, followed by mesangial proliferation. This resulted in enlarged glomeruli with loss of the characteristic lobular structure. Capillaries became randomly embedded into mesangial nodules, losing their filtration surface. Serum VEGF levels were increased, whereas endogenous VEGF production by podocytes was down-regulated. Taken together, this study shows that systemic VEGF interferes with the intraglomerular cross-talk between podocytes and the endocapillary compartment. It suppresses VEGF secretion by podocytes but cannot compensate for the deficit. VEGF from podocytes induces a directional effect, attracting the capillaries to the lobular surface, a relevant mechanism to optimize filtration surface. Systemic VEGF lacks this effect, leading to severe deterioration in glomerular architecture, similar to that seen in diabetic nephropathy.
 ...
PMID:Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. 1983 63

This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg(-1) x d(-1) ip and 30 mg/kg(-1) x d(-1), respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-beta(1), vascular endothelial growth factor, endothelin-1, TNF-alpha, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-alpha excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-alpha1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies.
 ...
PMID:Poly(Adenosine 5'-diphosphate-ribose) polymerase inhibition counteracts multiple manifestations of experimental type 1 diabetic nephropathy. 1985 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>