Abstract:
OBJECTIVE:Progressive fibrosis in the diabetic kidney is driven and sustained by a diverse range of profibrotic factors. This study examines the critical role of microRNAs (miRNAs) in the regulation of the key fibrotic mediators, TGF-β1 and TGF-β2. RESEARCH DESIGN AND METHODS:Rat proximal-tubular epithelial cells (NRK52E) were treated with TGF-β1 and TGF-β2 for 3 days, and expression of markers of epithelial-to-mesenchymal transition (EMT) and fibrogenesis were assessed by RT-PCR and Western blotting. The expression of miR-141 and miR-200a was also assessed, as was their role as translational repressors of TGF-β signaling. Finally, these pathways were explored in two different mouse models, representing early and advanced diabetic nephropathy. RESULTS:Both TGF-β1 and TGF-β2 induced EMT and fibrogenesis in NRK52E cells. TGF-β1 and TGF-β2 also downregulated expression of miR-200a. The importance of these changes was demonstrated by the finding that ectopic expression miR-200a downregulated smad-3 activity and the expression of matrix proteins and prevented TGF-β-dependent EMT. miR-200a also downregulated the expression of TGF-β2, via direct interaction with the 3' untranslated region of TGF-β2. The renal expression of miR-141 and miR-200a was also reduced in mouse models representing early and advanced kidney disease. CONCLUSIONS:miR-200a and miR-141 significantly impact on the development and progression of TGF-β-dependent EMT and fibrosis in vitro and in vivo. These miRNAs appear to be intricately involved in fibrogenesis, both as downstream mediators of TGF-β signaling and as components of feedback regulation, and as such represent important new targets for the prevention of progressive kidney disease in the context of diabetes.
journal_name
Diabetesjournal_title
Diabetesauthors
Wang B,Koh P,Winbanks C,Coughlan MT,McClelland A,Watson A,Jandeleit-Dahm K,Burns WC,Thomas MC,Cooper ME,Kantharidis Pdoi
10.2337/db10-0892subject
Has Abstractpub_date
2011-01-01 00:00:00pages
280-7issue
1eissn
0012-1797issn
1939-327Xpii
db10-0892journal_volume
60pub_type
杂志文章相关文献
DIABETES文献大全abstract::There has been a prejudice that diabetes modulates the function of saphenous vein in a manner that predisposes to bypass graft failure, although most of the evidence accrues from animal studies. We have investigated the effect of diabetes on the vasodilator responses and ultrastructure of saphenous vein harvested from...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.46.1.113
更新日期:1997-01-01 00:00:00
abstract::The presence of the enzyme aldose reductase is increasingly being linked to diabetic complications. The distribution of this enzyme in human cornea, lens, retina, and optic nerve has been studied using specific antibodies against purified human placental aldose reductase raised in both rabbit and goat. The antisera fr...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.6.562
更新日期:1984-06-01 00:00:00
abstract::In pancreatic beta-cells, glucose metabolism signals insulin secretion by altering the cellular array of messenger molecules. ATP is particularly important, given its role in regulating cation channel activity, exocytosis, and events dependent upon its hydrolysis. Uncoupling protein (UCP)-2 is proposed to catalyze a m...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.50.6.1302
更新日期:2001-06-01 00:00:00
abstract::The time course of islet cell antibodies (ICA) and serum C-peptides responses (CPRs) to oral glucose tolerance tests (OGTTs) were studied prospectively up to 60 (mean 35) mo in 32 ICA-positive subjects [28 with non-insulin-dependent diabetes (NIDDM) and 4 subjects with impaired glucose tolerance (IGT); mean age 45 yr]...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.36.4.510
更新日期:1987-04-01 00:00:00
abstract::To investigate the temporal relationship of diabetes-induced renal growth and its associated metabolic alterations to the early development of renal hyperfunction, parallel functional and metabolic studies were performed shortly after the onset of diabetes in rats. Hyperglycemia and hypoinsulinemia were evident 18 h a...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.36.1.80
更新日期:1987-01-01 00:00:00
abstract:OBJECTIVE:Most pancreatic endocrine cells derive from Ptf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db07-1558
更新日期:2008-09-01 00:00:00
abstract::Fifty male rats were made diabetic by a single injection of streptozotocin and were killed at periods varying from 1 to 12 mo. Ten saline-injected rats and three rats treated with 3-O-methylglucose and streptozotocin served as controls. Intraluminal changes in retinal vessels were studied by electron microscopy. In di...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.30.7.601
更新日期:1981-07-01 00:00:00
abstract:OBJECTIVE:Digenic causes of human disease are rarely reported. Insulin via its receptor, which is encoded by INSR, plays a key role in both metabolic and growth signaling pathways. Heterozygous INSR mutations are the most common cause of monogenic insulin resistance. However, growth retardation is only reported with ho...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-0787
更新日期:2009-12-01 00:00:00
abstract::The type I and type II isozymes of hexokinase coexist in insulin-sensitive tissues, such as cardiac and skeletal muscle and adipose tissue. Based on an early report that the purified type I isozyme was stable at 45 degrees C whereas the purified type II isozyme was not, investigators in a number of studies have used h...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.10.1544
更新日期:1998-10-01 00:00:00
abstract::The incretin hormones, glucagon-like peptide 1 and pituitary adenylyl cyclase-activating polypeptide, are proposed to activate a maitotoxin (MTX)-sensitive, Ca2+-dependent nonselective cation current in pancreatic beta-cells and insulinoma cells. This MTX-sensitive current is present in human beta-cells as well as in ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.7.1066
更新日期:1998-07-01 00:00:00
abstract::Recent evidence demonstrates that hypothalamic insulin signaling is required for inhibition of endogenous glucose production. The downstream mechanisms that are responsible for the effects of hypothalamic insulin receptor activation on hepatic fuel flux remain to be determined. To establish whether downregulation of n...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.10.2529
更新日期:2004-10-01 00:00:00
abstract:OBJECTIVE:A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 an...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-0506
更新日期:2009-10-01 00:00:00
abstract::In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either sa...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.10.1613
更新日期:1998-10-01 00:00:00
abstract::By closing ATP-sensitive K+ (K+-ATP) channels, glucose promotes depolarization-dependent Ca2+ entry and cytoplasmic free Ca2+ concentration ([Ca2+]i) rise in beta-cells. Ca2+-dependent exocytosis of insulin granules is then potentiated by a K+-ATP channel-independent action of glucose. The underlying mechanisms of thi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.11.1713
更新日期:1998-11-01 00:00:00
abstract::Dysfunctional T cells can mediate autoimmunity, but the inaccessibility of autoimmune tissues and the rarity of autoimmune T cells in the blood hinder their study. We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen system...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0946
更新日期:2017-08-01 00:00:00
abstract::These studies tested the hypothesis that physiological increments in plasma insulin concentrations have selective effects on the synthesis of hepatic proteins in humans. Leucine kinetics and fractional synthetic rates of albumin, fibrinogen, antithrombin III, and apoB-100 were determined in 6 normal subjects, on two d...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.7.995
更新日期:1993-07-01 00:00:00
abstract::Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-s...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0213
更新日期:2016-08-01 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:OBJECTIVE:The purpose of this work was to determine the pattern of genes regulated by peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (PGC-1 alpha) in human adipocytes and the involvement of PPARalpha and PPARgamma in PGC-1 alpha transcriptional action. RESEARCH DESIGN AND METHODS:Primary c...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1465
更新日期:2007-10-01 00:00:00
abstract:OBJECTIVE:White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduc...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-0929
更新日期:2010-01-01 00:00:00
abstract::Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases, but this is impaired in diabetes. We hypothesized that breaking advanced glycation end product (AGE) cross-links could improve remodeling in mesenteric resistance arteries in Zucker diabetic fatty (ZDF) rats compar...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-0750
更新日期:2012-06-01 00:00:00
abstract::I investigated biochemical parameters of sympathetic nerve function in spontaneously diabetic mice(C57 BL/KsJdb/db) and in their lean littermates. The concentration of norepinephrine (NE) in organs innervated by sympathetic nerves was significantly reduced in the heart, kidney, and salivary glands of mice (24 weeks ol...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.27.10.969
更新日期:1978-10-01 00:00:00
abstract::The strategy of positional cloning has been highly successful in identifying a number of single gene disorders that exhibit clear Mendelian patterns of inheritance. Positional cloning of insulin-dependent diabetes mellitus (IDDM) has been assisted by the expansion of molecular genetic tools and highly informative mark...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.2.139
更新日期:1995-02-01 00:00:00
abstract::Sirtuin 1 (SIRT1), an NAD(+)-dependent protein deacetylase, regulates a host of target proteins, including peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), a transcriptional coregulator that binds to numerous transcription factors in response to deacetylation to promote mitochondrial biogen...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db14-0325
更新日期:2015-02-01 00:00:00
abstract:OBJECTIVE:Physiologically elevated insulin concentrations promote access of macromolecules to skeletal muscle in dogs. We investigated whether insulin has a stimulating effect on the access of macromolecules to insulin-sensitive tissues in humans as well. RESEARCH DESIGN AND METHODS:In a randomized, controlled trial, ...
journal_title:Diabetes
pub_type: 杂志文章,随机对照试验
doi:10.2337/db07-0238
更新日期:2007-09-01 00:00:00
abstract::Troglitazone and pioglitazone, antidiabetic thiazolidinediones, are known to improve insulin resistance. However, the effect of these drugs on platelet aggregation remains unclear. The chemical structure of troglitazone contains vitamin E. Accordingly, we studied the effect of troglitazone, pioglitazone, and vitamin E...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.9.1494
更新日期:1998-09-01 00:00:00
abstract::Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial funct...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0117
更新日期:2012-12-01 00:00:00
abstract::Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress-sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.7.2179
更新日期:2005-07-01 00:00:00
abstract::Monoclonal antibodies to T-cell coreceptors have been shown to tolerise autoreactive T-cells and prevent or even reverse autoimmune pathology. In type 1 diabetes, there is a loss of insulin-secreting beta-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the function...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-0832
更新日期:2007-03-01 00:00:00
abstract::Because successful human islet transplantation requires large quantities of viable islets that must be separated from the highly immunogenic exocrine tissue and because handpicking is too time-consuming and laborious to be clinically relevant, a new approach for solving this problem has been established in rat models....
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.1.s146
更新日期:1989-01-01 00:00:00