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1.
Intern Med ; 56(6): 605-613, 2017.
Article in English | MEDLINE | ID: mdl-28321057

ABSTRACT

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitors are the most frequently prescribed oral hypoglycemic agents in Japan. Although a relationship between the efficacy of DPP-4 inhibitors and the body mass index (BMI) has been reported, this relationship is controversial. We investigated whether the BMI value affects the glucose-lowering efficacy of sitagliptin in obese Japanese patients with type 2 diabetes. Methods One hundred sixty-two outpatients with inadequate glycemic control were divided into four groups based on their baseline BMI values. They were then treated with sitagliptin (a DPP-4 inhibitor) for 3 months and followed-up for 12 months. Results Sitagliptin significantly reduced the hemoglobin A1c level (HbA1c: -0.71±0.55%) after 3 months, and continued to reduce the HbA1c level until 12 months. There was no significant difference in the efficacy of sitagliptin among the four BMI groups. A multiple linear regression analysis indicated that the factors contributing to the change in the HbA1c level were the baseline level of HbA1c and the homeostasis model assessment of ß-cell function (HOMA-ß). In terms of the relationship between the baseline BMI value and the efficacy of sitagliptin treatment, the number of patients who responded to sitagliptin treatment after 3 months was lowest in the group of patients with the highest BMI values. A multiple logistic regression analysis revealed that the baseline HOMA-ß function and HbA1c level and a baseline BMI value of ≥30 kg/m2 significantly contributed to the response to sitagliptin treatment. Conclusion The results indicated that sitagliptin treatment was effective in controlling glucose metabolism disorder in obese Japanese patients with type 2 diabetes. However, the efficacy of sitagliptin treatment might be attenuated in severely obese patients, such as those with a BMI value of ≥30 kg/m2.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Obesity/epidemiology , Aged , Blood Glucose/metabolism , Body Mass Index , Female , Glycated Hemoglobin/drug effects , Glycated Hemoglobin/metabolism , Humans , Japan , Male , Middle Aged , Prospective Studies , Sitagliptin Phosphate/therapeutic use
2.
Clin Exp Nephrol ; 16(5): 739-48, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22526486

ABSTRACT

BACKGROUND: Inflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I-type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy. METHODS: We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and α-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro. RESULTS: The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of α-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1ß and tumor necrosis factor-α but not with IL-4, transforming growth factor-ß and high glucose in cultured human macrophages. CONCLUSION: The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy.


Subject(s)
Diabetic Nephropathies/physiopathology , Macrophages/pathology , Sialic Acid Binding Ig-like Lectin 1/metabolism , Animals , Cells, Cultured , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/pathology , Disease Progression , Humans , Insulin/therapeutic use , Intercellular Adhesion Molecule-1/biosynthesis , Kidney/pathology , Male , Rats , Rats, Sprague-Dawley
3.
Clin Exp Nephrol ; 15(2): 212-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21181224

ABSTRACT

BACKGROUND: Hyperfiltration in the glomeruli have been considered to be an important cause of glomerular injury; however, the role of intercellular adhesion molecule (ICAM)-1 in the pathogenesis of glomerulosclerosis is not known. METHODS: To elucidate the effects of ICAM-1 depletion on hyperfiltration-induced glomerular disorder, we used subtotally nephrectomized ICAM-1(+/+) and ICAM-1(-/-) mice. We evaluated macrophage infiltration, mesangial matrix expansion, transforming growth factor (TGF)-ß and type IV collagen accumulation in glomeruli. RESULTS: Macrophage infiltration into the glomeruli and mesangial matrix expansion coincident with increased expression of both ICAM-1 and TGF-ß, and accumulation of type IV collagen were ameliorated in subtotally nephrectomized ICAM-1(-/-) mice compared to ICAM-1(+/+) mice. ICAM-1 depletion significantly reduced hyperfiltration-induced glomerular injury after renal ablation. CONCLUSIONS: Our present findings suggest that glomerular hyperfiltration is the leading cause of glomerulosclerosis, and it is mediated, at least in part, by ICAM-1 expression and macrophage infiltration.


Subject(s)
Intercellular Adhesion Molecule-1/physiology , Kidney Diseases/physiopathology , Kidney Glomerulus/metabolism , Animals , Collagen Type IV/biosynthesis , Kidney Diseases/pathology , Kidney Glomerulus/pathology , Macrophages/physiology , Male , Mice , Mice, Inbred C57BL , Nephrectomy , Transforming Growth Factor beta/biosynthesis
4.
Article in English | MEDLINE | ID: mdl-17487826

ABSTRACT

INTRODUCTION: Macrophages play critical roles in the development of atherosclerosis and diabetic nephropathy as well as many inflammatory diseases. Angiotensin II type 1 receptor antagonists (AIIA) are beneficial for the prevention of atherosclerosis and diabetic nephropathy suggesting that angiotensin II (Ang II) promotes the development of these diseases. It has recently been reported that Ang II exerts proinflammatory actions in vivo and in vitro. This study was aimed to clarify the direct effects of Ang II on monocytes/macrophages. MATERIALS AND METHODS: PMA-treated THP-1 cells, a human monocytic leukaemia cell line, were treated with Ang II (10-6 mol/L) for 24 hours with or without AIIA (CV11974). We evaluated gene expression profiles of these cells using DNA microarray system and quantified them by real-time RT-PCR. RESULTS: DNA microarray revealed that in total 19 genes, including monocyte chemoattractant protein (MCP)-2, were up-regulated by Ang II and down-regulated by AIIA. Real-time RT-PCR showed that up-regulation of MCP-2 with Ang II is blocked by the AIIA (CV11974) but not by an AT2-receptor antagonist. CONCLUSIONS: These results suggest that Ang II directly stimulates MCP-2 expression through AT1-receptors in activated macrophages. Ang II may contribute to the persistence or amplification of microinflammation in vessel walls, heart and kidney. Vasculoprotective or renoprotective effects of AIIA might partly depend on direct anti-inflammatory effects on macrophages.


Subject(s)
Angiotensin II/pharmacology , Macrophages/physiology , Monocyte Chemoattractant Proteins/genetics , Receptor, Angiotensin, Type 1/genetics , Vasoconstrictor Agents/pharmacology , Cell Line, Tumor , Chemokine CCL8 , Chemokines/genetics , Cytokines/genetics , Gene Expression/drug effects , Gene Expression/immunology , Gene Expression Profiling , Humans , Leukemia, Monocytic, Acute , Macrophages/cytology , Macrophages/drug effects , Monocytes/cytology , Monocytes/drug effects , Monocytes/physiology , Oligonucleotide Array Sequence Analysis , Receptor, Angiotensin, Type 2/genetics
5.
Intern Med ; 46(8): 495-9, 2007.
Article in English | MEDLINE | ID: mdl-17443042

ABSTRACT

A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocytes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occlusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.


Subject(s)
Hepatic Veno-Occlusive Disease/complications , Hepatic Veno-Occlusive Disease/diagnosis , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Fatal Outcome , Humans , Liver Failure/complications , Liver Failure/diagnosis , Male , Middle Aged
6.
Diabetes ; 56(2): 363-72, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17259380

ABSTRACT

Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SR-A(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-beta at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.


Subject(s)
Diabetic Nephropathies/metabolism , Inflammation/genetics , Kidney/metabolism , Scavenger Receptors, Class A/metabolism , Albuminuria , Animals , Collagen Type IV/metabolism , Creatinine/urine , Diabetes Mellitus, Experimental , Diabetic Nephropathies/genetics , Gene Expression , Glycation End Products, Advanced/metabolism , Mice , Mice, Knockout , Osteopontin/metabolism , RNA, Messenger/metabolism , Receptor for Advanced Glycation End Products , Receptors, Immunologic/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Scavenger Receptors, Class A/deficiency , Scavenger Receptors, Class A/genetics , Streptozocin , Transforming Growth Factor beta/metabolism
7.
J Am Soc Nephrol ; 16(11): 3326-38, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16177002

ABSTRACT

Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappaB activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappaB activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/prevention & control , Methotrexate/therapeutic use , Albuminuria/prevention & control , Animals , Male , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley
8.
J Biol Chem ; 279(3): 2085-90, 2004 Jan 16.
Article in English | MEDLINE | ID: mdl-14583626

ABSTRACT

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.


Subject(s)
Kidney/pathology , L-Selectin/physiology , Monocytes/physiology , Sulfotransferases/physiology , Ureteral Obstruction/pathology , Animals , Female , Immunoglobulin G/metabolism , Kidney/metabolism , Macrophages/physiology , Male , Mice , Sulfoglycosphingolipids/metabolism , Sulfotransferases/deficiency
9.
Diabetes ; 52(10): 2586-93, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14514644

ABSTRACT

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.


Subject(s)
Diabetic Nephropathies/etiology , Intercellular Adhesion Molecule-1/metabolism , Albuminuria , Animals , Blotting, Western , Collagen Type IV/metabolism , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Disease Susceptibility , Intercellular Adhesion Molecule-1/genetics , Kidney/metabolism , Kidney/pathology , Macrophages/pathology , Male , Mice , Mice, Knockout/genetics , Microscopy, Electron , Time Factors , Transforming Growth Factor beta/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
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