UMLS:C0011881 - FACTA Search

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)

Increased activation of specific protein kinase C (PKC) isoforms and increased nonenzymatic glycation of intracellular and extracellular proteins [the accumulation of advanced glycation end products (AGEs)] are major mechanistic pathways implicated in the pathogenesis of diabetic complications. Blocking PKC-beta(II) has been shown to decrease albuminuria in animal models of diabetes. To demonstrate a direct relationship between AGEs and the induction and translocation of PKC-beta(II), studies were carried out in rat neonatal mesangial cells, known to express PKC-beta(II) in association with rapid proliferation in post-natal development. Oxidative stress was studied by using the fluorescent probe dichlorfluorescein diacetate. Translocation of PKC-beta(II) was demonstrated by using immunofluorescence and Western blotting of fractionated mesangial cells. Induction of intracellular oxidative stress, increase in intracellular calcium, and cytosol to membrane PKC-beta(II) translocation (with no change in PKC-alpha) were demonstrated after exposure to AGE-rich proteins. These data support the hypothesis that AGEs cause mesangial oxidative stress and alterations in PKC-beta(II), changes that may ultimately contribute to phenotypic abnormalities associated with diabetic nephropathy.
...
PMID:AGEs induce oxidative stress and activate protein kinase C-beta(II) in neonatal mesangial cells. 1075 Dec 30

High-glucose-induced activation of mesangial cell protein kinase C (PKC) contributes significantly to the pathogenesis of diabetic nephropathy. Excess glucose metabolism through the polyol pathway leads to de novo synthesis of both diacylglyerol (DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-alpha, -beta, -delta, -epsilon, and -zeta activation/translocation observed within 48-h exposure to high glucose. Raised intracellular glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and cultured mesangial cells, PKC-beta appears to be the key isozyme required for the enhanced expression of transforming growth factor-beta(1), initiation of early accumulation of mesangial matrix protein, and increased microalbuminuria. Enhanced collagen IV expression by mesangial cells in response to vasoactive peptide hormone stimulation, e.g., endothelin-1, requires PKC-beta, -delta, -epsilon and -zeta. Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-zeta. Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.
...
PMID:Mesangial cell protein kinase C isozyme activation in the diabetic milieu. 1199 13

Oxidative stress is implicated to play an important role in the development of diabetic vascular complications, including diabetic nephropathy. It is unclear whether oxidative stress is primarily enhanced in the diabetic glomeruli or whether it is merely a consequence of diabetes-induced glomerular injury. To address this issue, we examined diabetic glomeruli to determine whether oxidative stress is enhanced, as well as examined the role of protein kinase C (PKC)-beta activation in modulating NADPH oxidase activity. Urinary 8-hydroxydeoxyguanosine excretion and its intense immune-reactive staining in the glomeruli were markedly higher in diabetic than in control rats, and these alterations were ameliorated by a treatment with a selective PKC-beta inhibitor, ruboxistaurin (RBX; LY333531) mesylate, without affecting glycemia. NADPH oxidase activity, which was significantly enhanced in diabetic glomeruli and the source of reactive oxygen species (ROS) generation, was also improved by RBX treatment by preventing the membranous translocation of p47phox and p67phox from cytoplasmic fraction without affecting their protein levels. Adenoviral-mediated PKC-beta(2) overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells. We now demonstrate that oxidative stress is primarily enhanced in the diabetic glomeruli due to a PKC-beta-dependent activation of NADPH oxidase resulting in ROS generation.
...
PMID:Translocation of glomerular p47phox and p67phox by protein kinase C-beta activation is required for oxidative stress in diabetic nephropathy. 1451 46

Kidney glomeruli are important targets of diabetic nephropathy. We hypothesized a high concentration of glucose could suppress glomerular endothelial nitric oxide synthase (eNOS) by a protein kinase C (PKC) mechanism, as has been found in other tissues. Mouse kidney slices (150-200 microm) were bathed in Hanks' solution with 100 microM L-arginine and exposed to either 5 or 20-30 mM D-glucose. Immunofluorescence identified only eNOS in normal mouse glomeruli. Measurements of glomerular NO concentration with NO-sensitive fluorescent dye (4,5-diaminofluorescein diacetate) using confocal microscopy and NO-sensitive microelectrodes verified that resting glomeruli had active production of NO that was inhibited by N(G)-nitro-L-arginine methyl ester. High-concentration (20-30 mM) D-glucose inhibited 60-70% of the NO production within 15-30 min; L-glucose at the same concentration did not have any effect. Inhibition of PKC-beta with 100 nM ruboxistaurin prevented eNOS suppression in high-glucose media. Activation of PKC with 100 nM phorbol ester also suppressed the glomerular NO concentration. We concluded that eNOS in the renal glomerular capillary endothelial cells is suppressed by activity of PKC at high-glucose concentrations comparable to those in diabetic animals and humans. The consequence is a rapid decline in the generation of NO in the glomerular endothelial cells in the presence of a high concentration of glucose.
...
PMID:High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. 1514 Jul 58

Although treatments for diabetic kidney disease are available, many patients still have progressive disease. More effective therapies are urgently needed. Novel agents currently under evaluation in clinical trials are described in this review. Sulodexide, a mixture of three glycosaminoglycans, appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix. Pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B(6). Alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection. Ruboxistaurin is an inhibitor of protein kinase C beta (PKC-beta), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models. These agents have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned.
...
PMID:The next generation of diabetic nephropathy therapies: an update. 1582 57

Tubulointerstitial macrophage accumulation is an important marker of prognosis that correlates closely with declining renal function in a range of human and experimental diseases, including diabetic nephropathy. These inflammatory cells are rich in the profibrotic growth factor TGF-beta such that their presence in areas of injury is frequently associated with tissue fibrosis. The migration of macrophages occurs in response to the site-specific production of chemokines, with osteopontin closely associated with their trafficking into the tubulointerstitium of the kidney. Although cell culture studies indicate that protein kinase C (PKC) mediates the expression of osteopontin, its role in the in vivo setting is unknown. Accordingly, Ren-2 control and diabetic rats that were treated with or without the specific PKC-beta isoform inhibitor ruboxistaurin (10 mg/kg per d) were examined. After 12 wk, diabetic rats showed increases in osteopontin expression in tubular epithelial cells of the cortex in association with macrophage infiltration, interstitial fibrosis, and activity of TGF-beta as indicated by the expression of its receptor activated protein phospho-Smad2 (P < 0.05 for all parameters). Ruboxistaurin treatment significantly attenuated these parameters (P < 0.05) in diabetic rats without affecting either BP or glycemic control. These findings suggest that osteopontin and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy and that inhibition of osteopontin expression may be one of the mechanisms by which inhibition of the beta-isoform of PKC confers a renoprotective effect.
...
PMID:Protein kinase Cbeta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental diabetic nephropathy. 1587 83

The protein kinase C (PKC)-beta isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-beta-deficient (PKC-beta(-/-)) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-beta(-/-) mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose-induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-beta(-/-) mice. Furthermore, the high-glucose-induced expression of the profibrotic cytokine transforming growth factor (TGF)-beta1 and connective tissue growth factor were significantly diminished in the diabetic PKC-beta(-/-) mice compared with diabetic wild-type mice, suggesting a role of the PKC-beta isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-beta(-/-) mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-beta(-/-) mice as previously demonstrated in the nonalbuminuric diabetic PKC-alpha(-/-) mice. In summary, the differential effects of PKC-beta deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-beta contributes to high-glucose-induced TGF-beta1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways.
...
PMID:Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. 1725 78

High ambient glucose activates intracellular signaling pathways to induce the expression of extracellular matrix and cytokines such as connective tissue growth factor (CTGF). Cell responses to CTGF in already glucose-stressed cells may act to transform the mesangial cell phenotype leading to the development of glomerulosclerosis. We analyzed cell signaling downstream of CTGF in high glucose-stressed mesangial cells to model signaling in the diabetic milieu. The addition of CTGF to primary human mesangial cells activates cell migration which is associated with a PKC-zeta-GSK3beta signaling axis. In high ambient glucose basal PKC-zeta and GSK3beta phosphorylation levels are selectively increased and CTGF-stimulated PKC-zeta and GSK3beta phosphorylation was impaired. These effects were not induced by osmotic changes. CTGF-driven profibrotic cell signaling as determined by p42/44 MAPK and Akt phosphorylation was unaffected by high glucose. Nonresponsiveness of the PKC-zeta-GSK3beta signaling axis suppressed effective remodeling of the microtubule network necessary to support cell migration. However, interestingly the cells remain plastic: modulation of glucose-induced PKC-beta activity in human mesangial cells reversed some of the pathological effects of glucose damage in these cells. We show that inhibition of PKC-beta with LY379196 and PKC-beta siRNA reduced basal PKC-zeta and GSK3beta phosphorylation in human mesangial cells exposed to high glucose. CTGF stimulation under these conditions again resulted in PKC-zeta phosphorylation and human mesangial cell migration. Regulation of PKC-zeta by PKC-beta in this instance may establish PKC-zeta as a target for constraining the progression of mesangial cell dysfunction in the pathogenesis of diabetic nephropathy.
...
PMID:Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose. 1732 98

In current study, the expressions of protein kinase C (PKC)-alpha, beta I and beta II as well as their correlation to the expression of transforming growth factor-beta I (TGF-beta I) and vascular endothelial growth factor (VEGF) were investigated in glomeruli of normal renal tissues taken from human kidney tumors and kidney tissues from patients with diabetic nephropathy (DN). The accumulation of glomerular extracellular matrix (ECM) was determined by PAS staining, the expressions of PKC-a, PKC-beta I, PKC-beta II, TGF-beta I and VEGF were measured by semi-quantitative immunohistochemistry. Our results showed that in glomeruli of normal renal tissues, PKC-alpha and beta II had a strong expression whereas the expression of PKC-beta I was weak; in glomeruli of DN patients, the expressions of PKC-alpha, PKC-beta I, VEGF and TGF-beta I and the accumulation of ECM increased significantly, but the expression of PKC-beta II decreased markedly. Meanwhile, the expressions of PKC-alpha and beta I had a positive correlation to the expressions of VEGF and TGF-beta I respectively, whereas PKC-beta II showed no correlation to VEGF and TGF-beta I. It is concluded that the expressions of PKC-alpha, beta I and beta II in glomeruli of normal subjects and DN patients are different. PKC-alpha seems to play a critical role in human DN by up-regulating VEGF expression, whereas PKC-beta I is relatively important for the up-regulation of TGF-beta I and the accumulation of ECM under diabetic conditions.
...
PMID:Different expressions of protein kinase C-alpha, beta I and beta II in glomeruli of diabetic nephropathy patients. 1735 79

Ruboxistaurin, an orally active protein kinase C beta (PKC beta) inhibitor, is a macrocyclic bisindolylmaleimide compound under development by Eli Lilly with potential as a therapy for diabetic macular oedema and other diabetic angiopathies, including diabetic retinopathy, diabetic peripheral neuropathy and diabetic nephropathy. Ruboxistaurin is awaiting approvals in the US and Europe for the treatment of diabetic retinopathy. Eli Lilly and Alcon entered into a long-term agreement to co-promote ruboxistaurin in the US and Puerto Rico for diabetic retinopathy. The agreement is subject to the US FDA's approval of the agent for this indication. Under the terms of the agreement, Alcon will assume primary responsibility for promotion to eye specialists including retinal specialists and general ophthalmologists, while Eli Lilly will be targeting endocrinologists and physicians. Subject to approval in the US, Eli Lilly will receive milestone and marketing payments from Alcon. Alcon in turn will receive compensation based on product sales. In December 2003, Eli Lilly signed a joint development and co-marketing agreement with Takeda Chemical Industries for ruboxistaurin in the Japanese market. Under the terms of the agreement, Eli Lilly Japan and Takeda will jointly develop ruboxistaurin in Japan, will file an NDA for diabetic peripheral neuropathy and diabetic retinopathy, and subsequently will market the drug in Japan. Ruboxistaurin was submitted for approval in Europe in the second quarter of 2006. The agent is also in phase II studies for the treatment of diabetic maculopathy (macular retinopathy) in Japan. Data from a phase III, 3-year study of ruboxistaurin in patients with moderate to severe diabetic retinopathy showed that ruboxistaurin markedly reduced the risk of sustained vision loss compared with placebo. This multicentre, randomised study, named PKC-DRS2 (Protein Kinase C-Diabetic Retinopathy Study 2), was conducted at 70 clinical sites and involved 685 patients with diabetic retinopathy. The agent is also in a phase II study in the US, Canada and Europe in patients with clinically significant macular oedema. The trial (B7A-MC-MBCU), which will evaluate oral administration of the drug using optical coherence tomography over a period of 18 months, is expected to enrol approximately 220 patients. This randomised, double-blind, placebo-controlled study was initiated in August 2005 and is expected to be completed in March 2008. Previously, results of the PKC-Diabetic Retinopathy Study (PKC-DRS) showed that ruboxistaurin at a dose of 32 mg/day has potential to reduce the risk of moderate vision loss especially in patients with diabetic macular oedema. This phase III, randomised, double-blind, multidose study in 252 patients with type 1 and type 2 diabetes receiving ruboxistaurin or placebo for 3-4 years evaluated the safety of the agent and its effect on progression of diabetic retinopathy, moderate vision loss and sustained moderate vision loss. The study was conducted at Joslin Diabetes Center and at centres in the US, Canada, Denmark, The Netherlands and the UK. In 2004, Eli Lilly presented new analysis of previously reported data for ruboxistaurin in diabetic macular oedema indicating that ruboxistaurin has the potential to decrease the progression of diabetic macular oedema involving the center of the macula. Positive results from the PKC Beta Inhibitor Diabetic Macular Edema (PKC-DMES) trial were reported in 2003. Eli Lilly expected to file for approval of ruboxistaurin for the treatment of diabetic peripheral neuropathy in the US and Europe in 2005. However, no development was reported for this indication. On 15 March 2007, Eli Lilly withdrew its marketing authorisation application for ruboxistaurin for diabetic retinopathy filed with EMEA in May 2006. Its current development status in the EU is unclear at this stage.
...
PMID:Ruboxistaurin: LY 333531. 1747 15

1 2 Next >>