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BioFactors (Oxford, England), Vol. 7, No. 1-2. (1998), pp. 69-76.
Abstract
Since diabetes now accounts for 35% of all new cases of end-stage renal disease in the United States, it is really important to prevent the onset of diabetic nephropathy. Activation of protein kinase C (PKC) is implicated to be one of the causal factors in the development of renal dysfunctions in diabetes. In this study, we have demonstrated that total diacylglycerol (DAG) contents and PKC activity in glomeruli were significantly increased in diabetic rats as compared to control rats, but intraperitoneal ...
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Journal of the American Society of Nephrology : JASN, Vol. 8, No. 3. (March 1997), pp. 426-435.
Abstract
Because d-alpha-tocopherol (vitamin E) has been shown to decrease diacylglycerol (DAG) levels and prevent the activation of protein kinase C (PKC), which is associated with retinal and renal dysfunctions in diabetes, the study presented here characterized the effect of d-alpha-tocopherol treatment to prevent glomerular hyperfiltration and increased albuminuria as well as PKC activities in streptozotocin (STZ)-induced diabetic rats. Two weeks after the induction of diabetes, total DAG content and PKC activity in glomeruli were significantly increased in diabetic rats by 106.4 ...
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J Am Soc Nephrol, Vol. 14, No. 5. (1 May 2003), pp. 1374-1382.
Abstract
10.1097/01.ASN.0000064500.89551.76 ...
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Diabetes care, Vol. 29, No. 4. (April 2006), pp. 864-868.
Abstract
OBJECTIVE: We investigated the contribution of PKC-beta gene (PRKCB1) polymorphisms to diabetic kidney disease in a prospective observational follow-up study. RESEARCH DESIGN AND METHODS: A total of 364 Japanese subjects with type 2 diabetes without overt proteinuria were enrolled during 1996-1998 and followed until 2004. Five single nucleotide polymorphisms (-1504C/T, -546C/G, -348A/G, -278C/T, and -238C/G) in the promoter region of PRKCB1 were genotyped. The end points were transition from stage to stage of diabetic nephropathy as a time-to-event outcome and the ...
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Diabetes research and clinical practice (2 November 2009)
by Kenichi Shikata, Masakazu Haneda, Daisuke Koya, et al.Yoshiki Suzuki, Yasuhiko Tomino, Kenichi Yamada, Shiro Maeda, Norito Kawakami, Takashi Uzu, Motonobu Nishimura, Chikage Sato, Daisuke Ogawa, Hirofumi Makino, DNETT-Japan Study Group
Abstract
The prevalence of end-stage renal disease (ESRD) is uprising in the paralleled with the increase of chronic kidney disease (CKD) patients. Diabetic nephropathy (DN) is the most important underlying disease of CKD and a leading cause of ESRD in Japan. Intensified multifactorial intervention in patients with type 2 diabetes with microalbuminuria slows the progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on DN with overt proteinuria. ...
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Diabetologia, Vol. 52, No. 10. (1 October 2009), pp. 2037-2045.
by D. Koya, M. Haneda, S. Inomata, et al.Y. Suzuki, D. Suzuki, H. Makino, K. Shikata, Y. Murakami, Y. Tomino, K. Yamada, S. I. Araki, A. Kashiwagi, R. Kikkawa, Low-Protein Diet Study Group
Abstract
AIMS/HYPOTHESIS: There is currently insufficient evidence to recommend a low-protein diet for type 2 diabetic patients with diabetic nephropathy. We assessed whether a low-protein diet could prevent the progression of diabetic nephropathy. METHODS: This was a multi-site parallel randomised controlled trial for prevention of diabetic nephropathy progression among 112 Japanese type 2 diabetic patients with overt nephropathy. It was conducted in Japan from 1 December 1997 to 30 April 2006. The participants were randomly assigned using a central computer-generated schedule to ...
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Nature reviews. Endocrinology, Vol. 5, No. 7. (19 July 2009), pp. 367-373.
Abstract
Sirtuin 1 (SIRT1), the mammalian homolog of SIR2, was originally identified as a NAD-dependent histone deacetylase, the activity of which is closely associated with lifespan under calorie restriction. Growing evidence suggests that SIRT1 regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates, and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. SIRT1 stimulates a glucose-dependent insulin secretion from pancreatic beta cells, and directly stimulates insulin signaling ...
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Journal of the American Society of Nephrology : JASN, Vol. 14, No. 4. (April 2003), pp. 863-872.
Abstract
Recent large clinical trials indicate that angiotensin-converting enzyme inhibitors (ACE-I) attenuate the detrimental outcome of progressive renal disease. The hemoregulatory tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP, AcSDKP) is hydrolyzed by ACE, and plasma Ac-SDKP level is increased by fivefold after treatment with ACE-I. Ac-SDKP was found to ameliorate cardiac and renal fibrosis in hypertensive animal models. However, the molecular mechanisms by which Ac-SDKP mediates anti-fibrotic effects remain unclear. This study is an examination of the interaction between Ac-SDKP and transforming growth factor-beta (TGF-beta), one ...
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American journal of physiology. Renal physiology, Vol. 296, No. 1. (January 2009)
by N. Deji, S. Kume, S. Araki, et al.M. Soumura, T. Sugimoto, K. Isshiki, M. Chin-Kanasaki, M. Sakaguchi, D. Koya, M. Haneda, A. Kashiwagi, T. Uzu
Abstract
Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat ...
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Diabetes, Vol. 54, No. 10. (1 October 2005), pp. 2983-2987.
Abstract
To estimate the frequency of remission/regression of microalbuminuria and to identify factors affecting such outcomes in Japanese patients with type 2 diabetes, we observed 216 patients with type 2 diabetes and microalbuminuria enrolled during an initial 2-year evaluation period for the next 6 years. Remission was defined as shift to normoalbuminuria and regression as a 50% reduction in urinary albumin excretion rate (AER) from one 2-year period to the next. Reduction of urinary AER was frequent, with a 6-year cumulative incidence ...
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Kidney International, Vol. 55, No. 5. (01 May 1999), pp. 1704-1712.
Abstract
BACKGROUND: An increase in the expression of transforming growth factor-beta 1 (TGF-beta 1) has been proposed to play an important role in the excessive production of extracellular matrix (ECM) proteins seen in diabetes. Because the linkage between glucose metabolism and ECM protein production was found in mesangial cells overexpressed with the brain-type glucose transporter (GLUT1), we hypothesized that TGF-beta 1 could affect glucose metabolism. METHODS: To prove this hypothesis, we examined the effect of TGF-beta 1 on glucose uptake, the first ...
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Diabetes research and clinical practice (21 October 2008)
Abstract
Diabetic nephropathy in type 2 diabetes is a leading cause of end-stage renal disease worldwide. Its early clinical sign is microalbuminuria, which is not only a predictor for progression of nephropathy but also an independent risk factor for cardiovascular disease. A few decades ago, diabetic nephropathy was believed to be progressive and irreversible. Thus, the main therapeutic objective for type 2 diabetic patients with microalbuminuria was to prevent progression to overt proteinuria. However, there is now growing evidence regarding remission/regression of ...
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Kidney international, Vol. 60, No. 4. (October 2001), pp. 1428-1434.
Abstract
BACKGROUND: Although genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, the definitive gene has not been identified. To identify the genetic marker for diabetic nephropathy, we examined the association between the (A-C)n dinucleotide repeat polymorphism upstream of the matrix metalloproteinase-9 (MMP-9) gene and diabetic nephropathy in a group of Japanese patients with type 2 diabetes. METHODS: Patients were divided into three groups based on their urinary albumin excretion rate (AER) and the ...
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Free radical biology & medicine, Vol. 40, No. 12. (15 June 2006), pp. 2175-2182.
Abstract
Oxidative stress-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and ...
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The Journal of biological chemistry, Vol. 282, No. 1. (5 January 2007), pp. 151-158.
by Shinji Kume, Masakazu Haneda, Keizo Kanasaki, et al.Toshiro Sugimoto, Shin-ichi Araki, Keiji Isshiki, Motohide Isono, Takashi Uzu, Leonard Guarente, Atsunori Kashiwagi, Daisuke Koya
Abstract
SIRT1, a class III histone deacetylase, is considered a key regulator of cell survival and apoptosis through its interaction with nuclear proteins. In this study, we have examined the likelihood and role of the interaction between SIRT1 and Smad7, which mediates transforming growth factor beta (TGFbeta)-induced apoptosis in renal glomerular mesangial cells. Immunoprecipitation analysis revealed that SIRT1 directly interacts with the N terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (Lys-64 and -70) on Smad7. In ...
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J Am Soc Nephrol, Vol. 18, No. 10. (1 October 2007), pp. 2715-2723.
by Shinji Kume, Takashi Uzu, Shin-Ichi Araki, et al.Toshiro Sugimoto, Keiji Isshiki, Masami Chin-Kanasaki, Masayoshi Sakaguchi, Naoto Kubota, Yasuo Terauchi, Takashi Kadowaki, Masakazu Haneda, Atsunori Kashiwagi, Daisuke Koya
Abstract
Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferatoractivated receptor gammadeficient (PPARgamma+/) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of ...
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Diabetes, Vol. 48, No. 3. (March 1999), pp. 595-602.
Abstract
An excessive production of extracellular matrix (ECM) proteins in glomerular mesangial cells is considered to be responsible for the development of mesangial expansion seen in diabetic nephropathy. Mechanical stretch due to glomerular hypertension has been proposed as one of the factors leading to an increase in the production of ECM proteins in mesangial cells, but the precise mechanism of stretch-induced overproduction of ECM proteins has not been elucidated. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) may play a ...
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Am J Kidney Dis, Vol. 41, No. 3 Suppl 1. (March 2003)
Abstract
BACKGROUND: Diabetic nephropathy, a kidney disease caused by diabetes, is the most devastating and money-consuming complication in patients with diabetes throughout the world. The cardinal lesion of diabetic nephropathy resides in renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is responsible for the development and progression of diabetic nephropathy through metabolic derangements, including increased oxidative stress, renal polyol formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases (MAPKs), and accumulation of advanced glycation end products, as well as such hemodynamic factors ...
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Am J Pathol, Vol. 166, No. 6. (June 2005), pp. 1629-1636.
Abstract
Despite the potentially protective effects of estrogen on bone and cardiovascular tissue as well as against kidney diseases, its effects on diabetic nephropathy are unknown. Here, we examined the therapeutic effectiveness of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, for preventing functional and histological alterations in the kidneys of db/db mice, a model of type 2 diabetes. In the first experiment, ovariectomized female db/db mice were treated with 17beta-estradiol for 8 weeks. The treatment significantly ameliorated albuminuria, attenuated weight gain, ...
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Diabetes, Vol. 53, No. 1. (January 2004), pp. 200-208.
Abstract
The thiazolidinedione (TZD) class of antidiabetic drugs, which are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, has been shown to possess potent anti-inflammatory and antineoplastic actions. Here, we show in mesangial cells that PPAR-gamma agonists inhibit fibronectin expression by transforming growth factor (TGF)-beta 1. TGF-beta 1 enhanced fibronectin mRNA expression, and this enhancement was abrogated by pretreatment with pioglitazone. Electrophoretic mobility shift assay identified that pioglitazone inhibited TGF-beta 1-induced DNA binding of activator protein-1 (AP-1). Pioglitazone inhibited AP-1 reporter activity but not ...
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The Journal of clinical investigation, Vol. 100, No. 1. (1 July 1997), pp. 115-126.
Abstract
Induction of protein kinase C (PKC) pathway in the vascular tissues by hyperglycemia has been associated with many of the cellular changes observed in the complications of diabetes. Recently, we have reported that the use of a novel, orally effective specific inhibitor of PKC beta isoform (LY333531) normalized many of the early retinal and renal hemodynamics in rat models of diabetes. In the present study, we have characterized a spectrum of biochemical and molecular abnormalities associated with chronic changes induced by ...
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Kidney international, Vol. 68, No. 3. (September 2005), pp. 972-984.
by Baoliang Guo, Ken Inoki, Motohide Isono, et al.Hiroyuki Mori, Keizo Kanasaki, Toshiro Sugimoto, Satoshi Akiba, Takashi Sato, Baofeng Yang, Ryuichi Kikkawa, Atsunori Kashiwagi, Masakazu Haneda, Daisuke Koya
Abstract
BACKGROUND: Receptor-regulated Smads and/or mitogen-activated protein kinases (MAPKs) are involved in transforming growth factor-beta (TGF-beta)-induced expression of various genes, including plasminogen activator inhibitor-1 (PAI-1). Because the sequence of the promoter region in rat PAI-1 gene differs from that in the human gene, we examined the mechanisms of TGF-beta-induced rat PAI-1 expression in rat mesangial cells. METHODS: TGF-beta1-induced PAI-1 and c-fos mRNA expressions were determined by Northern blot analysis. Activation of MAPKs and Smad proteins was evaluated by an immunoblot analysis. DNA ...
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FASEB J, Vol. 14, No. 3. (March 2000), pp. 439-447.
by D. Koya, M. Haneda, H. Nakagawa, et al.K. Isshiki, H. Sato, S. Maeda, T. Sugimoto, H. Yasuda, A. Kashiwagi, D. K. Ways, G. L. King, R. Kikkawa
Abstract
Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on ...
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Diabetes, Vol. 56, No. 6. (June 2007), pp. 1727-1730.
Abstract
OBJECTIVE: Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS: We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a ...
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