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.

■低钾性肾病(1)我们证明皮质和髓质中内皮素(ET)-1的产生上调，并且皮质和髓质中ET A型受体(ETA)和B型受体(ETB)的表达增加低钾肾病大鼠的髓质可改善低钾肾病的肾小管间质损伤和肾功能。相比之下，ETB 阻断可抑制肾 ET-1 产生和 ETA 表达，并改善肾小管间质损伤和肾 ET-1 产生和 ETA 表达，以及改善低钾性肾病的肾小管间质损伤和肾功能。这些结果表明，ET-1不仅可以通过直接激活ETA来诱导肾损伤，还可以通过刺激局部产生ET-1来诱导肾损伤。 (2)我们还证明，血管紧张素II拮抗作用可改善低钾性肾病的肾小管间质损伤和肾功能，并表明肾血管紧张素II的生成可能有助于低钾性肾小管间质损伤的发病机制。 ■血管活性因子的肾脏保护作用：肾上腺髓质素，一种有效的血管舒张剂肽和血管细胞的促存活因子，可能通过抑制肾脏产生 TNF-α 和白细胞介素 6 来改善肾缺血再灌注损伤中的肾小管坏死和细胞凋亡。■寻找糖尿病肾病的新候选基因：我们发现与肾脏发育和足细胞相关的基因表达发生变化与对照组相比，db/db 小鼠（2 型糖尿病模型）的结构、葡萄糖和脂质代谢以及氧化应激。改变可能与早期糖尿病肾小球病的发病机制有关。

项目成果

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）。

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）。

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