Departmental Bulletin Paper 4 糖尿病性臓器障害の基礎的検討 : 糖尿病性心筋症・腎症と小胞体ストレス(シンポジウム「糖尿病の合併症, 第699回新潟医学会)
Basic Studies of Diabetes Mellitus-diabetic Cardiomyopathy and Nephropathy

渡辺, 賢一  ,  Arun P, Lakshmanan  ,  Vivian, Soetikno  ,  Flori R, Sari  ,  Vijayakumar, Sukumaran  ,  Vijayasree V, Giridharan  ,  Rejina, Afrin  ,  Somasundaram, Arumugam  ,  Vengadesh, Karuppagounder  ,  Rajarajan A, Thandavarayan  ,  Vigneshwaran, Pitchaimani  ,  Remya, Sreedhar  ,  張馬, 梅蕾  ,  結城, 智史  ,  鈴木, 浩史  ,  宮下, しずか  ,  野本, 真由美  ,  中村, 隆志  ,  Watanabe, Kenichi  ,  Harima, Meilei  ,  Yuki, S  ,  Suzuki, Hiroshi  ,  Miyashita, Shizuka  ,  Nomoto, Mayumi  ,  Nakamura, Takashi

129 ( 7 )  , pp.354 - 363 , 2015-07 , 新潟医学会
心臓・腎臓など糖尿病性臓器障害の進展は, AMP活性化プロテインキナーゼ(AMPK)と小胞体ストレスが関与する. AMPKと小胞体ストレスは, 糖尿病性臓器障害における新治療薬の標的となりうることが示唆される. 糖尿病性腎症モデルの腎臓では酸化ストレス・炎症・線維化・脂肪沈着が亢進している. クルクミンはこれらを改善し, 安価な糖尿病腎症の予防薬・治療薬となりうることが示唆される.
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) in patients starting renal replacement therapy and affects ~ 40 % of type 1 and type 2 diabetic patients. Hyperglycemia plays a key role in the pathogenesis of long-term complications in diabetes mellitus. This process is influenced by individual susceptibility (i.e. genetic determinants) and by accelerating factors such as hypertension, inflammation and dyslipidemia, all of which are able to stimulate generation of reactive oxygen species (ROS). The increased of ROS production causes tissue damage through 4 major mechanisms: (1) increased flux of glucose and other sugars through the polyol pathway; (2) increased intracellular formation of advanced glycation end products (AGEs) and its receptor; receptor for AGEs (RAGE) and its activating ligands; (3) activation of protein kinase C (PKC) isoforms; and (4) overactivity of the hexosamine pathway. The PKC signaling pathway is the postulate that has received the most attention lately. PKC activation is involved in the regulation of vascular permeability and contractility, endothelial cell activation and vasoconstriction, extracellular matrix (ECM) synthesis and turnover, abnormal angiogenesis, excessive apoptosis, leucocyte adhesion, abnormal growth factor signaling and cytokine action, as well as abnormal cell growth and angiogenesis, all of which are involved in the pathophysiology of diabetic vascular complications. There is growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a role in the pathogenesis of DN. Sterol regulatory elemen-binding proteins (SREBPs) are transcription factors that regulate fatty acid and cholesterol synthesis. SREBPs belong to basic helix-loop-helix-leucine zipper family and activate the entire program of fatty acid and cholesterol synthesis in liver. Currently, there are three SREBPs isoforms that have been identified and characterized, namely, SREBP-1a, SREBP-1c, and SREBP-2. Multiple lines of evidence suggest that SREBP-1 and SREBP-2 have different relative effects on target genes. SREBP-1 preferentially activates genes involved in fatty acid and triglyceride synthesis, including Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), whereas SREBP-2 preferentially activates genes involved in cholesterol biosynthesis such as hydroxymethylglutaryl CoA synthase, hydroxymethylglutaryl CoA reductase, farnesyl diphosphate synthase, and squalene synthase. It has been demonstrated that there is an inverse correlation between 5' Adenosine monophosphate-activated protein kinase (AMPK) and SREBP-1c activity in hepatocytes and in livers of re-fed mice and ethanol-fed mice. In fact, AMPK is sufficient and necessary for the suppression of SREBP-1c proteolytic processing, nuclear translocation, and gene expression of target lipogenic enzymes in response to AMPK activators, such as polyphenols and metformin, in primary hepatocytes under conditions mimicking in vivo hyperglycemia and hyperinsulinemia. Curcumin is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. and has been used as a dietary spice and coloring agent in foods. It has a wide spectrum of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-obesity, and anticancer properties, prevents liver injury and kidney toxicity. We investigated the role of curcumin in experimental type 1 diabetic rats. Our results suggest that curcumin could ameliorate hyperglycemia, hyperlipidemia, inflammation and fibrosis in kidney tissues associated with DN which involved the dual blockade of both PKCα and PKCβ1 activities, reduced macrophage infiltration through the inhibition of NF-κB, and reduced renal triglyceride accumulation through the modulation of AMPK-SREBP pathway. Collectively, my present study provides data to support the role of curcumin in ameliorating DN in rats.

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