Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice.

Abstract:

AIMS/HYPOTHESIS:Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. METHODS:Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. RESULTS:Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellular-matrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. CONCLUSIONS/INTERPRETATION:Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Kuwabara T,Mori K,Mukoyama M,Kasahara M,Yokoi H,Saito Y,Ogawa Y,Imamaki H,Kawanishi T,Ishii A,Koga K,Mori KP,Kato Y,Sugawara A,Nakao K

doi

10.1007/s00125-012-2578-1

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

2256-66

issue

8

eissn

0012-186X

issn

1432-0428

journal_volume

55

pub_type

杂志文章
  • LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes.

    abstract:AIMS/HYPOTHESIS:Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown. ...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-015-3827-x

    authors: Cannon MV,Silljé HH,Sijbesma JW,Khan MA,Steffensen KR,van Gilst WH,de Boer RA

    更新日期:2016-03-01 00:00:00

  • Treatment of diabetes mellitus.

    abstract::New treatment strategies for subjects with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus are being developed. Pilot studies utilising insulin itself have been reported to prevent Type 1 diabetes in subjects likely, by immunogenetic and physiologic criteria, to develop clinically overt...

    journal_title:Diabetologia

    pub_type: 杂志文章,评审

    doi:10.1007/BF00586274

    authors: Robertson RP,Klein DJ

    更新日期:1992-12-01 00:00:00

  • Type I (insulin dependent) diabetes mellitus. Is there strong evidence for a non-HLA linked gene?

    abstract::A recent investigation of families containing two and three consecutive generations affected with Type I (insulin dependent) diabetes mellitus has led to speculation that there is a second susceptibility gene, not linked to the major histocompatibility complex. These families differ in important respects from families...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF00252759

    authors: Suarez BK,Van Eerdewegh P

    更新日期:1981-05-01 00:00:00

  • Differential binding of sulphated insulin to adipocytes and hepatocytes.

    abstract::The polymerization and precipitation of highly purified insulins which causes major problems in portable infusion systems does not occur with sulphated insulin. To compare the biological behaviour of sulphated insulin with that of a neutral highly purified monocomponent insulin, insulin receptor studies were performed...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF00273803

    authors: Zeuzem S,Taylor R,Agius L,Albisser AM,Alberti KG

    更新日期:1984-08-01 00:00:00

  • Obesity-associated intestinal insulin resistance is ameliorated after bariatric surgery.

    abstract:AIMS/HYPOTHESIS:The intestine is the main site for glucose absorption and it has been suggested that it exhibits insulin resistance. Bariatric surgery has been shown to reverse insulin resistance and type 2 diabetes, but its effects on human intestinal metabolism are unknown. Our aim was to evaluate the effects of insu...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-015-3501-3

    authors: Mäkinen J,Hannukainen JC,Karmi A,Immonen HM,Soinio M,Nelimarkka L,Savisto N,Helmiö M,Ovaska J,Salminen P,Iozzo P,Nuutila P

    更新日期:2015-05-01 00:00:00

  • Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease.

    abstract:AIMS/HYPOTHESIS:Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant chemokin...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-002-0879-5

    authors: Nicoletti F,Conget I,Di Mauro M,Di Marco R,Mazzarino MC,Bendtzen K,Messina A,Gomis R

    更新日期:2002-08-01 00:00:00

  • Cyclophosphamide treatment of female non-obese diabetic mice causes enhanced expression of inducible nitric oxide synthase and interferon-gamma, but not of interleukin-4.

    abstract::In pancreatic lesions of non-obese diabetic (NOD) mice the expression of inducible nitric oxide synthase (iNOS) and of the cytokines interferon-gamma and interleukin-4 were studied. Strong iNOS expression as determined at the level of transcription, translation and of enzyme activity was associated with destructive in...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF00418380

    authors: Rothe H,Faust A,Schade U,Kleemann R,Bosse G,Hibino T,Martin S,Kolb H

    更新日期:1994-11-01 00:00:00

  • High amniotic fluid erythropoietin levels are associated with an increased frequency of fetal and neonatal morbidity in type 1 diabetic pregnancies.

    abstract:AIMS/HYPOTHESIS:In this study we investigated whether chronic fetal hypoxia, as indicated by amniotic fluid erythropoietin levels, is associated with perinatal morbidity in type 1 diabetic pregnancies. METHODS:A total of 331 women with type 1 diabetes had at least one childbirth between 1995 and 2000. The amniotic flu...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-004-1515-3

    authors: Teramo K,Kari MA,Eronen M,Markkanen H,Hiilesmaa V

    更新日期:2004-10-01 00:00:00

  • Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells.

    abstract:AIMS/HYPOTHESIS:Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent data have linked the serine/threonine kinase protein kinase B (Akt) to matrix modulation. Here, we studied its role in high glucose-induced collagen elaboration by mesangial cells. METHODS:Primary rat mesangial cells were trea...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-007-0721-1

    authors: Wu D,Peng F,Zhang B,Ingram AJ,Gao B,Krepinsky JC

    更新日期:2007-09-01 00:00:00

  • NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.

    abstract::Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s001250050822

    authors: Pickup JC,Mattock MB,Chusney GD,Burt D

    更新日期:1997-11-01 00:00:00

  • Circulating prolactin concentrations and risk of type 2 diabetes in US women.

    abstract:AIMS/HYPOTHESIS:Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of prolactin are associated with risk of type 2 diabetes remains uncertain. METHODS:We analysed the prospective relationship b...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-018-4733-9

    authors: Li J,Rice MS,Huang T,Hankinson SE,Clevenger CV,Hu FB,Tworoger SS

    更新日期:2018-12-01 00:00:00

  • Increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy.

    abstract:AIMS/HYPOTHESIS:Maternal Type I (insulin-dependent) diabetes mellitus is associated with an increased risk for fetal malformations and spontaneous abortions. Although the pathogenic mechanism is not fully understood, reactive oxygen species have been shown to contribute to the pathogenesis in experimental studies. By m...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s001250051686

    authors: Cederberg J,Basu S,Eriksson UJ

    更新日期:2001-06-01 00:00:00

  • Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation.

    abstract::Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport syst...

    journal_title:Diabetologia

    pub_type: 传,历史文章,杂志文章,评审

    doi:10.1007/BF00400838

    authors: Häring HU,Kellerer M,Mosthaf L

    更新日期:1994-09-01 00:00:00

  • Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort.

    abstract:AIM/HYPOTHESIS:A strong association between susceptibility to type 2 diabetes and common variants of transcription factor 7-like 2 (TCF7L2), encoding an enteroendocrine transcription factor involved in glucose homeostasis, has been reported in three different populations (Iceland, Denmark and USA) by Grant et al. We ai...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-006-0477-z

    authors: van Vliet-Ostaptchouk JV,Shiri-Sverdlov R,Zhernakova A,Strengman E,van Haeften TW,Hofker MH,Wijmenga C

    更新日期:2007-01-01 00:00:00

  • 11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes.

    abstract::Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11beta-hydroxysteroid dehydrogenase ty...

    journal_title:Diabetologia

    pub_type: 杂志文章,评审

    doi:10.1007/s00125-003-1284-4

    authors: Stulnig TM,Waldhäusl W

    更新日期:2004-01-01 00:00:00

  • Insulin resistance is associated with high plasma ouabain-like immunoreactivity concentration in NIDDM.

    abstract::The aim of the present study was to elucidate the pathophysiologic significance of circulating ouabain as a link between insulin resistance (IR) and hypertension (HT) in NIDDM. Euglycaemic (4.5 mmol/l) hyperinsulinaemic (360-580 pmol/l) clamping was performed using an artificial endocrine pancreas. Plasma ouabain-like...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s001250050354

    authors: Wasada T,Kuroki H,Naruse M,Arii H,Maruyama A,Katsumori K,Saito S,Watanabe Y,Naruse K,Demura H

    更新日期:1995-07-01 00:00:00

  • The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children.

    abstract:AIMS/HYPOTHESIS:Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the dev...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-006-0363-8

    authors: Edge JA,Jakes RW,Roy Y,Hawkins M,Winter D,Ford-Adams ME,Murphy NP,Bergomi A,Widmer B,Dunger DB

    更新日期:2006-09-01 00:00:00

  • Increasing incidence of childhood-onset type I diabetes in 3 Baltic countries and Finland 1983-1998.

    abstract:AIMS/HYPOTHESIS:We aimed to study the incidence of Type I diabetes in 4 countries, Estonia, Latvia, Lithuania and Finland, during 1983-1998, focusing on the two separate periods of 1983-1990 and 1991-1998. METHODS:Population-based incidence data from nationwide diabetes registries were used. Crude and age-standardized...

    journal_title:Diabetologia

    pub_type: 杂志文章,多中心研究

    doi:10.1007/pl00002947

    authors: Podar T,Solntsev A,Karvonen M,Padaiga Z,Brigis G,Urbonaite B,Viik-Kajander M,Reunanen A,Tuomilehto J

    更新日期:2001-10-01 00:00:00

  • Mast cells and type VIII collagen in human diabetic nephropathy.

    abstract::Renal injury in diabetes mellitus is associated with progressive interstitial fibrosis and extracellular matrix accumulation. However, the phenotypes of cells forming the interstitial infiltrate in diabetic nephropathy have not been precisely defined. There is increasing evidence for the association of mast cells with...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF02658509

    authors: Rüger BM,Hasan Q,Greenhill NS,Davis PF,Dunbar PR,Neale TJ

    更新日期:1996-10-01 00:00:00

  • The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population.

    abstract:AIMS/HYPOTHESIS:The transcription factor upstream stimulatory factor 1 (USF1) regulates the expression of genes involved in glucose and lipid metabolism and has been associated with familial combined hyperlipidaemia. USF1 is located on chromosome 1q22-23, a region with evidence for linkage to type 2 diabetes and variou...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-005-1914-0

    authors: Ng MC,Miyake K,So WY,Poon EW,Lam VK,Li JK,Cox NJ,Bell GI,Chan JC

    更新日期:2005-10-01 00:00:00

  • Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70).

    abstract:AIMS/HYPOTHESIS:We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. METHODS:Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (U...

    journal_title:Diabetologia

    pub_type: 临床试验,杂志文章,多中心研究,随机对照试验

    doi:10.1007/s00125-005-1690-x

    authors: Davis TM,Wright AD,Mehta ZM,Cull CA,Stratton IM,Bottazzo GF,Bosi E,Mackay IR,Holman RR

    更新日期:2005-04-01 00:00:00

  • A low frequency of pancreatic islet insulin-expressing cells derived from cord blood stem cell allografts in humans.

    abstract:AIMS/HYPOTHESIS:We sought to establish if stem cells contained in cord blood cell allografts have the capacity to differentiate into insulin-expressing beta cells in humans. METHODS:We studied pancreases obtained at autopsy from individuals (n = 11) who had prior opposite-sex cord blood transplants to reconstitute hae...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-011-2071-2

    authors: Huang CJ,Butler AE,Moran A,Rao PN,Wagner JE,Blazar BR,Rizza RA,Manivel JC,Butler PC

    更新日期:2011-05-01 00:00:00

  • Effect of metergoline, a powerful and long-acting antiserotoninergic agent, on insulin secretion in normal subjects and in patients with chemical diabetes.

    abstract::The effect of metergoline on insulin secretion has been evaluated in normal subjects and in patients with chemical diabetes. The repeated administration of metergoline, 2 mg at four-hour intervals to give a total of 24 mg, has enhanced insulin secretion in response to i.v. glucose in normal subjects but not in chemica...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF00429842

    authors: Pontiroli AE,Viberti GC,Tognetti A,Pozza G

    更新日期:1975-04-01 00:00:00

  • Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents.

    abstract:AIMS/HYPOTHESIS:There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many case-control mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants a...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-009-1510-9

    authors: Byrne EM,McRae AF,Duffy DL,Zhao ZZ,Martin NG,Whitfield JB,Visscher PM,Montgomery GW

    更新日期:2009-11-01 00:00:00

  • Abnormal regulation of sympathetic nervous activity and heart rate after oral glucose in type 1 (insulin-dependent) diabetic patients.

    abstract::Oral glucose administration increased plasma noradrenaline concentration significantly in seven normal subjects (p less than 0.02), whereas in six young short-term Type 1 diabetic patients without complications plasma noradrenaline did not change. Basal plasma noradrenaline did not differ between the two groups. In th...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF00279937

    authors: Hegedüs L,Christensen NJ,Sestoft L

    更新日期:1983-09-01 00:00:00

  • Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk.

    abstract:AIMS/HYPOTHESIS:Translation of genetic association signals into molecular mechanisms for diabetes has been slow. The glucokinase regulatory protein (GKRP; gene symbol GCKR) P446L variant, associated with inverse modulation of glucose- and lipid-related traits, has been shown to alter the kinetics of glucokinase (GCK) i...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-011-2348-5

    authors: Rees MG,Wincovitch S,Schultz J,Waterstradt R,Beer NL,Baltrusch S,Collins FS,Gloyn AL

    更新日期:2012-01-01 00:00:00

  • Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice.

    abstract:AIMS/HYPOTHESIS:Dysfunction of lipid metabolism in white adipose tissue can substantially interfere with health and quality of life, for example in obesity and associated metabolic diseases. Therefore, it is important to characterise pathways that regulate lipid handling in adipocytes and determine how they affect meta...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-016-4152-8

    authors: Kaltenecker D,Mueller KM,Benedikt P,Feiler U,Themanns M,Schlederer M,Kenner L,Schweiger M,Haemmerle G,Moriggl R

    更新日期:2017-02-01 00:00:00

  • Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans.

    abstract::The involvement of nitric oxide as an intracellular messenger in the control of insulin secretion from pancreatic Beta cells was studied in rat islets of Langerhans by measuring: (i) nitric oxide generation in response to physiological insulin secretagogues; (ii) the effects of inhibitors of nitric oxide synthesis on ...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/BF02221676

    authors: Jones PM,Persaud SJ,Bjaaland T,Pearson JD,Howell SL

    更新日期:1992-11-01 00:00:00

  • Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients.

    abstract:AIMS/HYPOTHESIS:Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-015-3808-0

    authors: Favaro E,Carpanetto A,Caorsi C,Giovarelli M,Angelini C,Cavallo-Perin P,Tetta C,Camussi G,Zanone MM

    更新日期:2016-02-01 00:00:00

  • Spousal cardiometabolic risk factors and incidence of type 2 diabetes: a prospective analysis from the English Longitudinal Study of Ageing.

    abstract:AIMS/HYPOTHESIS:In the UK, more than one million people have undiagnosed diabetes and an additional five million are at high risk of developing the disease. Given that early identification of these people is key for both primary and secondary prevention, new screening approaches are needed. Since spouses resemble each ...

    journal_title:Diabetologia

    pub_type: 杂志文章

    doi:10.1007/s00125-018-4587-1

    authors: Nielsen J,Hulman A,Witte DR

    更新日期:2018-07-01 00:00:00