2003 Fiscal Year Annual Research Report

糸球体上皮細胞における酸化ストレス制御による糖尿病性腎症の尿蛋白減少作用

Research Project

Project/Area Number	14571014
Research Institution	The University of Tokyo
Principal Investigator	藤乗嗣泰東京大学, 医学部附属病院, 助手 (50292917)
Keywords	diabetic nephropathy / NADPH oxidase / nitric oxide / superoxide / angiotensin II / podocyte / proteinuria / oxidative stress
Research Abstract	尿蛋白は糖尿病性腎症の糸球体障害度の指標であり、増悪進展因子でもある。尿蛋白の機序としで酸化ストレスによる糸球体基底膜の障害があるが、その産生源は好中球やマクロファージとともに糸球体細胞、特にpodocyteのNADPH oxidaseが重要である。糖尿病性腎症では腎臓組織angiotensin IIとTGF-α,IL1βの増加によりNADPH oxidase発現が亢進し、活性酸素産生が増加しているので、ACE阻害薬やAT1受容体遮断薬あるいはp38MAPK阻害薬によりNADPH oxidaseとそのラジカル産生を減少させると蛋白尿は減少した。抗血小板薬ジピリダモールは直接NADPH oxidaseの発現を抑制し、またPDE阻害を介しでNOSの発現を増加し、ACE阻害薬との併用により糖尿病性腎症のアルブミン尿をさらに減少した(Kidney Int 61:186-194,2002;Diabotes Res Clin Pract 2003;59:83-92)。 NADPH oxidase阻害薬のapocyninは糸球体上皮細胞のNADPH oxidaseを抑制し,SOD mimeticsよりも強くラジカル産生を減少し蛋白尿を改善した。Nephrinは糸球体上皮細胞の細胞膜上のlipid raftに存在し、コレステロールの増大はnephrinの発現に影響する。高コレステロール食負荷糖尿病ラットではICAM-1による糸球体内浸潤細胞の増加と糸球体上皮細胞NADPH oxidase亢進により酸化ストレスが増加し、尿蛋白はより増加した。ラジカル消去作用をもつSU剤のgliclazideはglibenclamideに比べ、糸球体NADPH oxidaseの制御と糸球体浸潤細胞の減少から酸化ストレスを有意に抑制した(Kidney Int 2004;65:951-960)。単離糸球体上皮細胞をangiotensn IIで培養するとNADPH oxidase, actin, nephrin, ZO-1などの発現が変化し、糸球体上皮細胞での酸化ストレスによるactinの変化がslit membraneの構造変化やnephrinの発現低下による蛋白尿につながる。近位尿細管の機能は糖尿病性腎症で障害されている。糖尿病性腎症で減少した近位尿細管のmegalinはACE阻害薬やARBで回復し、megalinによるアルブミンのendocytosisが改善し微量アルブミン尿が減少する(Hypertens Res 2003;26:413-419)。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] Maristela Lika Onozato, Akihiro Tojo, Atsuo Goto, Toshiro Fujita: "Radical scavenging effect of gliclazide in diabetic rats fed with a high cholesterol diet."Kidney Int. 65(3). 951-960 (2004)
[Publications] Tojo A, Onozato ML, Kurihara H, Sakai T, Goto A, Fujita T: "Angiotensin II Blockade Restores Albumin Reabsorption in Proximal Tubule of Diabetic Rat."Hypertension Res. 26. 413-419 (2003)
[Publications] Onozato ML, Tojo A, Goto A, Fujita T: "Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy."Diabetes Res Clin Pract. 59. 83-92 (2003)
[Publications] Tojo A, Fujita T, Wilcox CS: "Omapatrilat : still a promise in salt-sensitive hypertension?"J Hypertens. 21(1). 31-32 (2003)
[Publications] Yamasaki M, Kawai J, Nakaoka T, Ogita T, Tojo A, Fujita T: "Adrenomedullin overexpression to inhibit cuff-induced arterial intimal formation."Hypertension. 41(2). 302-307 (2003)
[Publications] Ueno T, Kaname S, Takaichi K, Nagase M, Tojo A, Onozato ML, Fujita T: "Lox-1, an oxidized low-density lipoprotein receptor, was upregulated in the kidneys of chronic renal failure rats."Hypertens Res. 26. 117-122 (2003)
[Publications] Takeda M, Noshiro R, Onozato ML, Tojo A, Hasannejad H, Huang XL, Narikawa S, Endou H: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors."Eur J Pharmacol. 483(2-3). 133-138 (2004)
[Publications] MIYASHITA K, TOJO A, KIMURA K, GOTO A, OMATA M, NISHIYAMA K, FUJITA T: "Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients."Hypertens Res. 27. 79-84 (2004)
[Publications] Onozato ML, Tojo A, Ogura S, Asaba K, Goto A, Fujita T: "Primary amyloidosis with multiple pulmonary nodular lesions and IgA nephropathy-like renal involvement."Clin Nephrol. 60. 134-138 (2003)
[Publications] Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, Piyachaturawat P, Endou H: "Interaction of human and at rat organic anion transporter 2 with various cephalosporin antibiotics."Eur J Pharmacol. 465(1-2). 1-7 (2003)
[Publications] Asaba K, Tojo A, Onozato ML, Mimura N, Kido M, Goto A, Endo H, Fujita T: "Fibrillary glomerulonephritis associated with essential thrombocytosis."Clin Exp Nephrol. 7. 296-300 (2003)
[Publications] Alebouyeh M, Takeda M, Onozato ML, Tojo A, Noshiro R, Hasannejad H, Inatomi J, Narikawa S, Huang XL, Khamdang S, Anzai N, Endou H: "Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites."J Pharmacol Sci.. 93(4). 430-436 (2003)
[Publications] 藤乗嗣泰, 小野里マリステラリカ, 浅羽研介: "NO : nitric oxide. Annual Review腎臓2004"中外医学社(伊藤克己、遠藤仁、御手洗哲也、東原英二、秋澤忠男編). 251(1-8) (2004)

2003 Fiscal Year Annual Research Report

糸球体上皮細胞における酸化ストレス制御による糖尿病性腎症の尿蛋白減少作用

Principal Investigator

藤乗 嗣泰 東京大学, 医学部附属病院, 助手 (50292917)

Research Products

[Publications] Maristela Lika Onozato, Akihiro Tojo, Atsuo Goto, Toshiro Fujita: "Radical scavenging effect of gliclazide in diabetic rats fed with a high cholesterol diet."Kidney Int. 65(3). 951-960 (2004)

[Publications] Tojo A, Onozato ML, Kurihara H, Sakai T, Goto A, Fujita T: "Angiotensin II Blockade Restores Albumin Reabsorption in Proximal Tubule of Diabetic Rat."Hypertension Res. 26. 413-419 (2003)

[Publications] Onozato ML, Tojo A, Goto A, Fujita T: "Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy."Diabetes Res Clin Pract. 59. 83-92 (2003)

[Publications] Tojo A, Fujita T, Wilcox CS: "Omapatrilat : still a promise in salt-sensitive hypertension?"J Hypertens. 21(1). 31-32 (2003)

[Publications] Yamasaki M, Kawai J, Nakaoka T, Ogita T, Tojo A, Fujita T: "Adrenomedullin overexpression to inhibit cuff-induced arterial intimal formation."Hypertension. 41(2). 302-307 (2003)

[Publications] Ueno T, Kaname S, Takaichi K, Nagase M, Tojo A, Onozato ML, Fujita T: "Lox-1, an oxidized low-density lipoprotein receptor, was upregulated in the kidneys of chronic renal failure rats."Hypertens Res. 26. 117-122 (2003)

[Publications] Takeda M, Noshiro R, Onozato ML, Tojo A, Hasannejad H, Huang XL, Narikawa S, Endou H: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors."Eur J Pharmacol. 483(2-3). 133-138 (2004)

[Publications] MIYASHITA K, TOJO A, KIMURA K, GOTO A, OMATA M, NISHIYAMA K, FUJITA T: "Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients."Hypertens Res. 27. 79-84 (2004)

[Publications] Onozato ML, Tojo A, Ogura S, Asaba K, Goto A, Fujita T: "Primary amyloidosis with multiple pulmonary nodular lesions and IgA nephropathy-like renal involvement."Clin Nephrol. 60. 134-138 (2003)

[Publications] Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, Piyachaturawat P, Endou H: "Interaction of human and at rat organic anion transporter 2 with various cephalosporin antibiotics."Eur J Pharmacol. 465(1-2). 1-7 (2003)

[Publications] Asaba K, Tojo A, Onozato ML, Mimura N, Kido M, Goto A, Endo H, Fujita T: "Fibrillary glomerulonephritis associated with essential thrombocytosis."Clin Exp Nephrol. 7. 296-300 (2003)

[Publications] 藤乗嗣泰, 小野里マリステラリカ, 浅羽研介: "NO : nitric oxide. Annual Review腎臓2004"中外医学社(伊藤克己、遠藤仁、御手洗哲也、東原英二、秋澤忠男 編). 251(1-8) (2004)

藤乗嗣泰東京大学, 医学部附属病院, 助手 (50292917)

[Publications] 藤乗嗣泰, 小野里マリステラリカ, 浅羽研介: "NO : nitric oxide. Annual Review腎臓2004"中外医学社(伊藤克己、遠藤仁、御手洗哲也、東原英二、秋澤忠男編). 251(1-8) (2004)