Mechanism of Renal Injury Induced by Metabolic Factors and Prevention of the Injury by Vasoprotective Factors.

代谢因素诱发肾损伤的机制及血管保护因素预防肾损伤。

• 批准号: 14571044
• 负责人: SUGA Shinichi
• 金额: $ 2.24万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571044/
• 关键词: renal tubulointerstitial injury; hypokalemic nephropathy; hypoxia; endothelin; angiotensin II; adrenomedullin; ischemic; reperfusion; diabetic nephropathy; アドレノメジュリン; 血管新生; 低カリウム血症; アンジオテンシII; 血管内皮; 国際情報交換; 米国

■Hypokalemic Nephropathy(1)We demonstrated an up-regulation of endothelin (ET)-1 production in the cortex and medulla, and an increase in the expression of the ET type A receptor (ETA) and type B receptor (ETB) in the medulla of rats with hypokalemic nephropathy. ETA blockade ameliorated renal tubulointerstitial injury and renal function in hypokalemic nephropathy. ETA blockade ameliorated renal ET-1 production. By contrast, ETB blockade suppressed renal ET-1 production and ETA expression as well as improved renal tubulointerstitial injury and renal ET-1 production and ETA expression as well as improved renal tubulointerstitial injury and renal function in hypokalemic nephropathy. These results suggested that ET-1 can induce renal injury not only via direct activation of ETA, but also by stimulating local production of ET-1 via ETB.(2)We also demonstrated that angiotensin II antagonism ameliorates tubulointerstitial injury and renal function in hypokalemic nephropathy, and suggested that renal angiotensin II generation may contribute to the pathogenesis of hypokalemic tubulointerstitial injury.■Renoprotection by Vasoactive Factors : Adrenomedullin, a potent vasorelaxing peptide and a prosurvival factor for vascular cells, ameliorates tubular necrosis and apoptosis in ischemic reperfusion injury of the kidney possibly by suppressing renal production of TNF-α and interleukin-6.■Searching New Candidate Genes for Diabetic Nephropathy : We found an alteration in the expression of genes related to kidney development and podocyte structure as well as glucose and lipid metabolism and oxidative stress in db/db mice, a model of type 2 diabetes, when compared to the control. This alteration might be related to pathogenesis of early diabetic glomerulopathy.

■降低性肾病（1）我们证明了皮质和髓质中内皮素（ET）-1的产生的上调，以及A型A型受体（ETA）和B型受体（ETA）和甲状腺中Medulla中大鼠肾脏症状肾病性肾病性肾病性疾病的表达的增加。 ETA封锁改善了肾病性肾病的肾小管造成损伤和肾功能。 ETA封锁改善了肾脏ET-1的产生。相比之下，ETB阻滞抑制了肾脏ET-1的产生和ETA表达，以及改善的肾脏管隆性损伤和肾脏ET-1产生和ETA的表达，以及改善的肾细胞胞质症状损伤和肾功能低下肾病。这些结果表明，ET-1不仅可以通过直接激活ETA诱导肾脏损伤，而且还可以通过ETB刺激ET-1的局部产生。（2）我们还证明，血管紧张素II拮抗剂可以改善结核性损伤和肾功能性的肾脏性肾脏性肾病性肾病的肾脏性肾脏疾病的生成率促进了肾脏肾上腺素II造成肾脏素的生成率，并提示 injury.■Renoprotection by Vasoactive Factors: Adrenomedullin, a potential vasorelaxing peptide and a prosurvival factor for vascular cells, ameliorates tuberostatic necrosis and apoptosis in ischemic reperfusion injury of the kidney possible by suppressing renal production of TNF-α and interleukin-6.■Searching New Candidate Genes for Diabetic肾病：与对照相比，我们发现与肾脏发育和足细胞结构相关的基因表达改变了与肾脏发育和足细胞结构以及葡萄糖和脂质代谢以及与对照相比的2型糖尿病模型的葡萄糖和脂质代谢和氧化应激。这种改变可能与早期糖尿病肾小球病的发病机理有关。

项目成果

徳留 健: "Different effects of high glucose and insulin on cultured cardiac myocyte hypertrophy and fibroblast proliferation"Metabolism. 印刷中. (2004)

Ken Tokudome：“高葡萄糖和胰岛素对培养的心肌细胞肥大和成纤维细胞增殖的不同影响”代谢（2004）。

菅 真一: "Endothelin A receptor blockade and endothelin B receptor blockade improve hypokalemic nephropathy by different mechanisms"Journal of the American Society of Nephrology. (印刷中). (2003)

Shinichi Suga：“内皮素 A 受体阻断和内皮素 B 受体阻断通过不同机制改善低钾性肾病”美国肾病学会杂志（2003 年）。

Suga S, et al.: "Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium-deficiency."Kidney International. 61・3. 951-958 (2002)

Suga S 等人：“血管紧张素 II 1 型受体阻断可改善慢性缺钾引起的肾小管间质损伤。”61·3 (2002)。

堀尾 武史: "Gene expression, secretion, and autocrine action of C-type natriuretic peptide in cultured adult rat cardiac fibroblasts"Endocrinology. (印刷中). (2003)

Takeshi Horio：“培养的成年大鼠心脏成纤维细胞中 C 型钠尿肽的基因表达、分泌和自分泌作用”内分泌学（2003 年）。

T.Horio, T.Tokudome, T.Maki, F.Yoshihara, S.Suga, T.Nishikimi, M.Kojima, Y.Kawano, K.Kanagawa: "Gene Expression, Secretion, and Autocrine Action of C-type Natriuretic Peptide in Cultured Adult Rat Cardiac Fibroblasts."Endocrinology. 144. 2279-2284 (2003)

T.Horio、T.Tokudome、T.Maki、F.Yoshihara、S.Suga、T.Nishikimi、M.Kojima、Y.Kawano、K.Kanakawa：“C 型利尿钠的基因表达、分泌和自分泌作用