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)

Glomerular hyperfiltration is thought to play an important role in the genesis of diabetic nephropathy. While hyperfiltration is well documented in early type I diabetes, the evidence for hyperfiltration in type II diabetes is conflicting. We investigated 16 nonproteinuric patients with recently diagnosed type II diabetes. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as inulin clearance (CIN) and p-aminohippuric acid clearance (CPAH) using a constant infusion technique. Lean body mass was measured by densitometry (weighing under water). Renal hemodynamics were also measured in 31 healthy volunteers and six obese nondiabetic individuals. Median GFR in diabetics (133 mL/min/1.73 m2; range, 95 to 165) was significantly (P < 0.01) higher than in obese nondiabetic controls (median, 118; range, 95 to 139). Elevated GFR (ie, > 95th percentile of nonobese healthy controls) was found in 44% of patients. When GFR was factored for lean body mass, it was elevated in 50%. GFR did not correlate with fasting glucose, hemoglobin A1C (HbA1C), insulin-like growth factors, IGF-1 and IGF-2, or somatomedin-binding protein (SMBP). The findings document that hyperfiltration is common in recent-onset type II diabetics.
 ...
PMID:Renal hemodynamics in recent-onset type II diabetes. 141 1

Disturbed function of the axis hypothalamus-growth hormone-somatomeding C (IGF-1) plays an important role in the development of diabetic angiopathy. Patients with insuline dependent diabetes show increased secretion on GH but secretion of IGF-1 may be normal, decreased or increased. These disturbances are especially distinct in the prepubescent period when susceptibility to develop complications is bigger. Increased secretion of GH and IGF-1 plays an essential role in the development of retinopathy and diabetic nephropathy. The paper explains the role of GH in controlling glycaemia and in the development of vascular complications during diabetes.
 ...
PMID:[The role of growth hormone in the development of complications in insulin-dependent diabetes]. 206 73

Major findings with regard to the somatostatin-growth hormone (GH)-insulin-like growth factor (IGF-1) axis and diabetes are summarized. GH hypersecretion and reduced circulating IGF-1 levels are prevalent in insulin-dependent diabetes. Somatostatin improves metabolism in insulin-dependent diabetics. Insulin resistance and poor metabolic regulation, which may partly be due to hypersecretion of GH, are believed to accelerate the development of diabetic angiopathy. Diabetic hypersomatotrophinemia may be due to hepatic resistance to GH and increased hepatic production of IGF-1-binding protein-1 (IGFBP-1), leading to reduced levels of circulating IGF-1 and further stimulation of GH production. Studies in vitro and in diabetics suggest a causal link between diabetic hypersomatotrophinemia and diabetic angiopathy. In vitro evidence for the involvement of IGF-1 in diabetic angiopathy is reviewed. Also reviewed is evidence, from rat and human studies, of the possible involvement of GH and IGF-1 in diabetic nephropathy. The role of somatostatin in late diabetic vascular complications remains to be elucidated.
 ...
PMID:Somatostatin, growth hormone, insulin-like growth factor-1, and diabetes: friends or foes? 876 94

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
 ...
PMID:How does hyperglycaemia predispose to diabetic nephropathy? 930 34

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.
 ...
PMID:[Diabetic nephropathy--recent advances in its mechanism and treatment]. 1019 39

Diabetic nephropathy is characterised by a progressive accumulation of extracellular matrix within the glomerular mesangium and the interstitium. The pathogenesis of this fibrotic process is still poorly understood, but in vitro and in vivo data suggest that TGF-B plays a key role. Local overproduction of TGF-B could be secondary to a synthesis of diacylglycerol, polyols, or glucosamines. It may also be secondary to an accumulation of advanced glycosylation end-products which modify the functions of neighbouring cells. Moreover, clinical as well as experimental data for TGF-B suggest that angiotensin II has a profibrotic effect; and it has been clearly demonstrated that angiotensin-converting enzyme inhibitors have a beneficial effect in patients with insulin-dependent diabetes mellitus. Other molecules such as endothelin-1, lipid peroxidation products, or IGF-1 may also play a role in this fibrotic process. Finally, heavy proteinuria secondary to glomerular lesions enhances the accumulation of extracellular matrix within the interstitium, probably through modifications of tubular cell functions, thereby inducing the release of pro-inflammatory and profibrotic molecules.
 ...
PMID:Growth factors, cytokines, and renal fibrosis during the course of diabetic nephropathy. 1092 69

Diabetic nephropathy is the leading cause of end-stage renal disease in western or westernised countries and the largest contributor to the total cost of diabetes care around the world. In addition to the development of diabetic nephropathy and end-stage renal failure, diabetic patients with evidence of albuminuria have a much higher risk of developing myocardial infarctions, cerebrovascular accidents, severe progressive retinopathy, and peripheral and autonomic neuropathy. A cumulative incidence of diabetic nephropathy has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients, although more recent studies have demonstrated a substantial reduction of its incidence. Before the onset of overt proteinuria, there are several renal functional changes, including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetic nephropathy. It has been postulated that diabetic nephropathy occurs as a result of the interplay of metabolic and haemodynamic factors in the renal microcirculation. Hyperglycaemia plays a pivotal role in the pathogenesis of diabetic renal disease, but genetic factors are also of crucial importance. The accumulation of advanced glycosilation end products (AGEPs), the activation of isoforms of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycaemia damages vessels. Growth factors (i.e. TGF-b, IGF-1, VEGF) may also play an important role in the pathogenesis. There is a familial clustering of diabetic kidney disease: a number of gene loci have been investigated to try to explain the genetic susceptibility to this complication. The two main treatment strategies for prevention of diabetic nephropathy are improved glycaemic control and blood pressure lowering, particularly using drugs such angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Many potential treatment modalities in preventing and treating diabetic nephropathy are presently being evaluated; some of them will possibly be available in the near future in order to try to modify the natural course of kidney involvement and disease in patients with diabetes.
 ...
PMID:Kidney involvement and disease in patients with diabetes. 1268 18

Renal mesangial cell hypertrophy is a characteristic of diabetic nephropathy as well as a response to renal stress or injury. Because hypertrophy is a result of increased protein content per cell without DNA replication, those proteins that control the cell cycle, such as the cyclin kinase inhibitor p21, represent fertile ground for studying the mechanism of this structural alteration. A key role for p21 in promoting mesangial cell (MC) hypertrophy has been established using p21 knockout mouse models. Furthermore, some of the biologic effects of IGF-1, including cell proliferation, have been shown to be positively influenced by p21. In an attempt to begin to translate these findings ultimately to the bedside, methods to attenuate p21 levels in wild-type kidney cells were examined. With the use of a phosphorothioated antisense oligodeoxynucleotide (ODN) to p21, which has previously been shown to decrease specifically and effectively p21 protein levels in a variety of cell types, it is shown that attenuation of p21 in MC leads to a dose-dependent reduction of hypertrophy in the milieu of hyperglycemic culture media. Furthermore, the hypertrophic effect of the IGF-1 on MC is also attenuated using the same antisense p21 ODN. There was no evidence of apoptosis or other toxicity in MC transfected with the concentrations of antisense p21 ODN used in these experiments. Because the use of antisense ODN in human disease is already established in other medical disciplines, the stage is now set for the use of antisense p21 ODN to attenuate renal cell hypertrophy in vivo, leading to a new strategy for treatment of diabetic nephropathy and other diseases characterized by MC hypertrophy.
 ...
PMID:Exogenous attenuation of p21(Waf1/Cip1) decreases mesangial cell hypertrophy as a result of hyperglycemia and IGF-1. 1497 86

Recently we demonstrated that IGF-1 expression is increased in the diabetic kidney and that it may involve in renal hypertrophy and extracellular matrix protein (ECM) accumulation in mesangial cells as seen in diabetic glomerulopathy. The present study investigates the molecular mechanism(s) of IGF-1 and Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway in the regulation of fibronectin and cyclin D1 expression and survival of renal mesangial cells. A proteomic approach is also employed to identify protein targets of IGF-1 signaling via GSK-3beta inhibition in mesangial cells. We show that IGF-1 (100 ng/ml) significantly increases the protein kinase Akt/PKB activity (1.5-2-fold, p<0.05) within 1-5 minutes, which is completely blocked by the presence of 100 nM Wortmannin (phosphatidyl-inositol 3-kinase inhibitor). Akt activation is coupled with Ser9 phosphorylation and inactivation of its down-stream target GSK-3beta. IGF-1 increases the cyclic AMP-responsive element (CRE) binding transcription factor CREB phosphorylation at Ser 133 and CRE-binding activity in mesangial cells, which parallels cyclin D1 and fibronectin expressions. Both proteins are known to have CRE-sequences in their promoter regions upstream of the transcription start site. Suppression of GSK-3beta by SB216763 (100 nM) increases CREB phosphorylation, cyclin D1 and fibronectin levels. Two dimensional gel electrophoresis followed by MALDI-TOF mass spectrometric analysis of mesangial proteins reveals that IGF-1 treatment or an inhibition of GSK-3beta increases the expression of the phosphorylated Ser/Thr binding signal adapter protein 14-3-3zeta. Immuno-precipitation of 14-3-3zeta followed by Western blotting validates the association of phosphorylated GSK-3beta with 14-3-3zeta in renal mesangial cells. Stable expression of a constitutively active GSK-3beta(Ser9Ala) induces cell death while overexpression of HA-tagged 14-3-3zeta increases cell viability as measured by MTT assays. These results indicate that the Akt/GSK-3beta pathway and the adapter protein 14-3-3zeta may play an important role in IGF-1 signaling and survival of mesangial cells in diabetic nephropathy.
 ...
PMID:Proteomic identification of 14-3-3zeta as an adapter for IGF-1 and Akt/GSK-3beta signaling and survival of renal mesangial cells. 1720 Jun 89

Renal hypertrophy and deposition of extracellular matrix proteins are consistent findings in diabetic nephropathy and these processes can be halted or reversed by euglycemic control. Using DNA microarray analysis of glomerular RNA from control and diabetic rats we found that the expression levels of insulin-like growth factor 1 receptor (IGF-1R) were increased while those of suppressor of cytokine signaling 2 (SOCS2) and STAT5 were decreased. All of these changes were normalized by islet cell transplantation. Overexpression of SOCS2 in rat mesangial cells inhibited IGF-1-induced activation of extracellular signal-regulated kinase, which subsequently reduced type IV collagen and DNA synthesis, an effect due to interaction of SOCS2 with IGF-1R. Inhibition of SOCS2 overexpression by small interfering RNA suppressed IGF-1R-mediated actions by preventing phosphorylation of tyrosine 317 in the p66Shc adaptor protein; however, overexpression of either SOCS1 or SOCS3 did not affect IGF-1R signaling. Insulin directly increased STAT5 and SOCS2 expression in mesangial cells. This study shows that insulin can inhibit the mitogenic action of IGF-1 in mesangial cells by regulating STAT5/SOCS2 expression. Insulin deficiency may contribute to the mesangial expansion found in diabetes through reduced STAT5/SOCS2 expression.
 ...
PMID:Insulin regulates SOCS2 expression and the mitogenic effect of IGF-1 in mesangial cells. 1900 12


1 2 Next >>