Abstract:
OBJECTIVE:Accumulation of glomerular matrix proteins is central to the pathogenesis of diabetic nephropathy, with resident mesangial cells (MCs) known to upregulate matrix protein synthesis in response to high glucose. Because activation of the GTPase RhoA has been implicated in matrix upregulation, we studied its role in induction of the matrix protein fibronectin in diabetic MCs and in vivo in diabetic nephropathy. RESEARCH DESIGN AND METHODS:Glucose (30 mmol/l)-induced RhoA/Rho-kinase, AP-1 activation, and fibronectin upregulation were assessed by immunoblotting, luciferase, electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, real-time PCR, Northern blots, and immunofluorescence. Streptozotocin-induced diabetic rats were treated with the rho-kinase inhibitor fasudil, which was compared with enalapril, and functional and pathologic parameters were assessed. RESULTS:Glucose led to RhoA and downstream Rho-kinase activation. Mannitol was without effect. Activity of the transcription factor AP-1, increased in diabetic MCs and kidneys, is important in the profibrotic effects of glucose, and this was dependent on Rho-kinase signaling. Upregulation of fibronectin by glucose, shown to be mediated by activator protein-1 (AP-1), was prevented by Rho-kinase inhibition. RhoA siRNA and dominant-negative RhoA also markedly attenuated fibronectin upregulation by high glucose. Applicability of these findings were tested in vivo. Fasudil prevented glomerular fibronectin upregulation, glomerular sclerosis, and proteinuria in diabetic rats, with effectiveness similar to enalapril. CONCLUSIONS:High glucose activates RhoA/Rho-kinase in MCs, leading to downstream AP-1 activation and fibronectin induction. Inhibition of this pathway in vivo prevents the pathologic changes of diabetic nephropathy, supporting a potential role for inhibitors of RhoA/Rho in the treatment of diabetic renal disease.
journal_name
Diabetesjournal_title
Diabetesauthors
Peng F,Wu D,Gao B,Ingram AJ,Zhang B,Chorneyko K,McKenzie R,Krepinsky JCdoi
10.2337/db07-1149subject
Has Abstractpub_date
2008-06-01 00:00:00pages
1683-92issue
6eissn
0012-1797issn
1939-327Xpii
db07-1149journal_volume
57pub_type
杂志文章相关文献
DIABETES文献大全abstract::T-1095A and T-1095 are synthetic agents derived from phlorizin, a specific inhibitor of Na+-glucose cotransporters (SGLTs). Unlike phlorizin, T-1095 is absorbed into the circulation via oral administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney. Orally administe...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.9.1794
更新日期:1999-09-01 00:00:00
abstract::Cysteamine (300 mg/kg) administered subcutaneously depletes pancreatic somatostatin to 36% of control levels, but does not alter pancreatic insulin or glucagon content. Although perfusion of pancreata from normal animals with glucose (300 mg/dl) markedly stimulated somatostatin release, pancreata from cysteamine-treat...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.32.4.377
更新日期:1983-04-01 00:00:00
abstract::The mechanism of protection from type 1 diabetes conferred by regulatory T-cells induced by oral insulin treatment of NOD mice is not well understood. We demonstrate that oral insulin feeding of NOD mice induces the function of insulin B-chain reactive CD4+ regulatory T-cells, which compete with diabetogenic effector ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.9.1720
更新日期:1999-09-01 00:00:00
abstract::To investigate the short-term effects of didecanoyl-L-alpha-phosphatidylcholine on the nasal mucosa and the mechanism by which didecanoyl-L-alpha-phosphatidylcholine enhances the nasal absorption of insulin, an in vitro model was developed. The mucosa from the posterior part of the rabbit nasal septum was mounted in a...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.7.1032
更新日期:1993-07-01 00:00:00
abstract:OBJECTIVE:Recently, several drugs have been shown to exert beneficial effects for metabolic syndrome through mild regulation of mitochondrial function. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism. RESEARCH DESIGN AND METHODS:Mitochondrial membrane potential...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-0223
更新日期:2010-01-01 00:00:00
abstract::Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects wi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0234
更新日期:2016-11-01 00:00:00
abstract::Growth medium containing serum from young diabetic subjects caused a significant stimulation both of cell proliferation and of the outgrowth in cultures of rabbit aortic medial cells above that noted with normal human sera. The addition to the sera of guinea-pig human growth hormones antibody caused a marked inhibitio...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.26.8.798
更新日期:1977-08-01 00:00:00
abstract::Recent work suggests that insulin may exert both positive and negative feedback directly on pancreatic beta-cells. To investigate the hypothesis that insulin modulates beta-cell metabolism, mouse islets and beta-cell clusters were loaded with rhodamine 123 to dynamically monitor mitochondrial membrane potential (Delta...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.7.1765
更新日期:2004-07-01 00:00:00
abstract::Glucose tolerance depends on a complex interaction among insulin secretion from the beta-cells, clearance of the hormone, and the actions of insulin to accelerate glucose disappearance and inhibit endogenous glucose production. An additional factor, less well recognized, is the ability of glucose per se, independent o...
journal_title:Diabetes
pub_type: 杂志文章,评审
doi:10.2337/diab.38.12.1512
更新日期:1989-12-01 00:00:00
abstract::Myo-Inositol depletion as a result of hyperglycemia is considered one of the leading contributors to chronic diabetic complications. We investigated the possible mechanisms through which elevated extracellular glucose levels affect the loss of intracellular myo-inositol in rat lens. Short-term incubation (up to 4 h) i...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.12.1737
更新日期:1993-12-01 00:00:00
abstract::Low birth weight is a well-established risk factor for type 2 diabetes, but the risk at high birth weight levels remains uncertain. Potential sex differences in the associations are unexplored. We investigated whether sex influences the association of birth weight and adult type 2 diabetes, using a cohort of 113,801 m...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db15-0494
更新日期:2015-12-01 00:00:00
abstract:OBJECTIVE:Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS:For the measu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db08-1147
更新日期:2009-03-01 00:00:00
abstract::Repeated large-volume blood withdrawals started at a young age previously appeared to correct lymphopenia and prevent diabetes in Ottawa diabetes-prone BB (BBdp) rats. Therefore, we sought an early effect 24 h after withdrawal of 25% of estimated blood volume and then reexamined the long-term effects in BBdp rats. The...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.39.9.1099
更新日期:1990-09-01 00:00:00
abstract::The cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) gene is implicated as an important regulator of body weight in mice and humans and is therefore a candidate gene for human obesity. Here, we characterize common CIDEA gene polymorphisms and investigate them for association with obesi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.10.3032
更新日期:2005-10-01 00:00:00
abstract::It is unknown whether and to what extent changes in various endothelial functions and adrenergic responsiveness are related to the development of microvascular complications in type 1 diabetes. Therefore, endothelium-dependent and endothelium-independent vasodilatation, endothelium-dependent hemostatic factors, and on...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.6.1300
更新日期:1999-06-01 00:00:00
abstract::An epidemic of obesity and type 2 diabetes is linked with the increase in consumption of fructose-containing sugars, such as sucrose and high-fructose corn syrup. In mammalian cells, fructose is metabolized predominantly via phosphorylation to fructose-1 phosphate by ketohexokinase (KHK) or by alternative pathways. He...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db14-0411
更新日期:2015-02-01 00:00:00
abstract::Hypoadiponectinemia has been widely observed in patients with gestational diabetes mellitus (GDM). To investigate the causal role of hypoadiponectinemia in GDM, adiponectin gene knockout (Adipoq-/- ) and wild-type (WT) mice were crossed to produce pregnant mouse models with or without adiponectin deficiency. Adenovira...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1096
更新日期:2017-05-01 00:00:00
abstract::We determined islet amyloid polypeptide (IAPP) response in plasma to oral and intravenous glucose administration and intravenous insulin injection in nondiabetic subjects. Moreover, we studied the effect of somatostatin analogue SMS 201-995 on glucose-induced IAPP secretion in nondiabetic subjects. Plasma IAPP concent...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.39.5.639
更新日期:1990-05-01 00:00:00
abstract::Long-term insulin secretion was investigated in seven biohybrid capillary devices seeded with canine islets. Approximately 50,000 islets could be isolated from a single canine pancreas using collagenase digestion in conjunction with the recently described Velcro technique. Devices were perfused with tissue culture med...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.34.9.850
更新日期:1985-09-01 00:00:00
abstract::Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.49.6.1057
更新日期:2000-06-01 00:00:00
abstract::Neonatal rats injected with streptozocin (STZ, 100 mg/kg) at birth exhibited an acute diabetes followed by a spontaneous remission. We have previously shown that this recovery from neonatal diabetes is due to B-cell regeneration and reaccumulation of pancreatic insulin stores starting from 3 to 5 days after birth. The...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.34.6.574
更新日期:1985-06-01 00:00:00
abstract::Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focuse...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-1541
更新日期:2012-06-01 00:00:00
abstract::The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functi...
journal_title:Diabetes
pub_type: 杂志文章,评审
doi:10.2337/diabetes.47.4.507
更新日期:1998-04-01 00:00:00
abstract::Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese ado...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0889
更新日期:2013-03-01 00:00:00
abstract::The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene effect appears to be modified by environmental factors. We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein respon...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2337/diab.46.12.2082
更新日期:1997-12-01 00:00:00
abstract::Diabetes complications are caused by hyperglycemia. Hyperglycemia results in increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) has been ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.8.2424
更新日期:2005-08-01 00:00:00
abstract::Activation of thermogenic beige adipocytes has recently emerged as a promising therapeutic target in obesity and diabetes. Relevant human models for beige adipocyte differentiation are essential to implement such therapeutic strategies. We report a straightforward and efficient protocol to generate functional human be...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1107
更新日期:2017-06-01 00:00:00
abstract::Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in β-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in β-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with β-cell-specific deletion of Tsc2 (βTsc...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-0970
更新日期:2014-09-01 00:00:00
abstract:OBJECTIVE:Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db07-1690
更新日期:2008-12-01 00:00:00
abstract:OBJECTIVE:Insulin stimulates glucose transport in skeletal muscle by GLUT4 translocation from intracellular compartments to sarcolemma and t-tubules. We studied in living animals the recruitment of GLUT4 vesicles in more detail than previously done and, for the first time, analyzed the steady-state recycling and subseq...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1578
更新日期:2008-02-01 00:00:00