Investigation for anti-renal fibrotic effects of lipid-binding proteins and lipid-activated nuclear receptors and search for new therapeutic reagents

研究脂质结合蛋白和脂质激活核受体的抗肾纤维化作用并寻找新的治疗试剂

• 批准号: 21591024
• 负责人: KIMURA Hideki
• 金额: $ 2.83万
• 依托单位: University of Fukui
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591024/
• 关键词: 腎臓学; ペルオキシゾーム増殖剤応答性受容体; 脂肪酸結合蛋白; 尿細管上皮細胞; メサンギウム細胞; 炎症; アンジテンシンII受容体拮抗薬; 肝X受容体(LXR); ペルオキシゾーム増殖薬活性化受容体(PPAR); PAI-1; MCP-1; 低酸素; TNF-α; TGF-β; ファルネソイドX受容体(FXR); プラスミノーゲンアクチベーターインヒビタ-1(PAI-1); プラスミノーゲンアクチベーターインヒビター1(PAI-1)

Presence and activities of peroxisome proliferator-activated receptor(PPAR)-δandγwere confirmed in human proximal renal tubular epithelial cells and mesangial cells which inflammatory insults targeted mainly during progression of renal injury. An angiotensin II receptor blocker, telmisartan was shown to have PPAR-δandγ-induced transcriptional activities and increase expression of their target genes such as fatty acid-binding protein(FABP) and liver X receptor. Telmisartan also decreased gene expression of monocyte chemoattractant protein-1(MCP-1). In the mouse immortalized proximal renal tubular cell line with over-expression of human liver-type FABP, a putative transporter of PPAR ligands, mouse PPAR-δwas up-regulated and MCP-1 down-regulated. These results suggest that some bioactive molecules with a potential to affect function and dynamism of PPAR and FABP are candidates of new therapeutic reagents for chronic kidney disease.

过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，过氧化物酶体增殖物激活受体）-δ和γ在人近端肾小管上皮细胞和系膜细胞中的存在和活性被证实，炎症损伤主要是在肾损伤的进展过程中发生的。替米沙坦是一种血管紧张素II受体阻滞剂，研究表明其具有PPAR-δ和γ诱导的转录活性，并增加其靶基因（如脂肪酸结合蛋白（FABP）和肝脏X受体）的表达。替米沙坦还降低了单核细胞趋化蛋白-1（MCP-1）的基因表达。在过表达人肝型FABP（一种假定的PPAR配体转运蛋白）的小鼠永生化近端肾小管细胞系中，小鼠PPAR-δ表达上调，MCP-1表达下调。这些结果表明，一些生物活性分子的潜在影响的功能和动力学的PPAR和FABP是慢性肾脏疾病的新的治疗药物的候选人。

项目成果

Discrete Regulation of VEGF-A and-C in Human Proximal Renal Tubular Cells under Hypoxic and/or Inflammatory Conditions.-Inhibitory Effects of Glucocorticoids on Basal and Inducible VEGF Expression-

缺氧和/或炎症条件下人近端肾小管细胞中 VEGF-A 和-C 的离散调节。-糖皮质激素对基础和诱导 VEGF 表达的抑制作用-

• 发表时间: 2010
• 作者: SaitoA;Kaseda R;Hosoiima M;Sato H;Tanaka M;Tanizaki J;川本進也;Hideki Kimura
• 通讯作者: Hideki Kimura

Tubulointerstitial nephritis with IgM-positive plasmacytoid large lymphocyte infiltration in a patient with primary biliary cirrhosis and Sjogren's syndrome

原发性胆汁性肝硬化伴干燥综合征患者肾小管间质性肾炎伴 IgM 阳性浆细胞样大淋巴细胞浸润

• 发表时间: 2010
• 期刊: Clin Nephrol
• 影响因子: 1.1
• 作者: Takahashi N;Kimura H
• 通讯作者: Kimura H

Overexpression of Human Liver-Fatty Acid-Binding Protein endogenously Enhances Peroxisome Proliferator Activated Receptor-αActivity possibly via inducing Hepatocyte Nuclear Factor-4αin Immortalized Mouse Proximal Renal Tubular Cells

人肝脏脂肪酸结合蛋白的过度表达可能通过诱导永生化小鼠近端肾小管细胞中的肝细胞核因子-4α内源性增强过氧化物酶体增殖物激活受体-α活性

• 发表时间: 2011
• 作者: Kazuhito Totsune;他7名;Kimura H
• 通讯作者: Kimura H

Smaller LDL size as a possible risk factor for the prevalence of coronary artery diseases in hemodialysis patients-Associations of CETP and the hepatic lipase gene polymorphism with LDL size

较小的LDL大小可能是血液透析患者冠状动脉疾病患病的危险因素-CETP和肝脂肪酶基因多态性与LDL大小的关联

• DOI: 10.1111/j.1440-1797.2011.01454.x
• 发表时间: 2011
• 期刊: Nephrology(Carlton)
• 作者: Kimura H;Miyazaki R;Imura T;Masunaga S;Shimada A;Mikami D;Kasuno K;Takahashi N;Hirano T;Yoshida H
• 通讯作者: Yoshida H

Tubulointerstitial nephritis with IgM-positive plasmacytoid large lymphocyte infiltration in a patient with primary biliary cirrhosis and Sjogren's syndrome.

原发性胆汁性肝硬化和干燥综合征患者的肾小管间质性肾炎伴 IgM 阳性浆细胞样大淋巴细胞浸润。

• 发表时间: 2010
• 期刊: Clin Nephrol
• 影响因子: 1.1
• 作者: Tanizaki J;Okamoto I;Okamoto K;Takezawa K;Kuwata K;Yamaguchi H;Nakagawa K;Naoki Takahashi
• 通讯作者: Naoki Takahashi