Investigation on anti-inflammatory effects of lipid-binding proteins and lipophilic transcriptional factors in progression of renal injury.

脂质结合蛋白和亲脂性转录因子在肾损伤进展中的抗炎作用的研究。

• 批准号: 17590823
• 负责人: KIMURA Hideki
• 金额: $ 2.18万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590823/
• 关键词: renal fibrosis; human proximal renal tubular cells; MCP-1; TNF-α; peroxisome proliferator-ativiated receptors; hypoxia; fatty acid-binding proteins; PAI-1; 脂質転送蛋白; 抗炎症作用; hypoxia; proximal renal tubular cells; lipid-binding proteins; 脂質親和性転写因

1. Effects of hypoxia and inflammation on expression of lipophilic transcriptional factors in cultured human proximal renal tubular epithelial cells (HPTECs).(1) In HPTECs under normoxia and hypoxia, mRNA amounts of lipophilic transcriptional factors (PPAR-α, β, γ, RXR-α, β, RAR-α, β, FXR) were determined using cDNA array system. Under normoxia, all the genes were significantly expressed in the cells. Relative mRNA amounts of RXR, FXR, and PPAR-γ were 10.1, 5.4, and 2.1, respectively, when the amount of PPA-α was set to 1.0. Hypoxia reduced PPA-α by 20%, PPAR-γ by 70% and RX-α by 30% at mRNA levels, while FXR mRNA expression was unchanged under hypoxia.(2) Hypoxia reduced PPAR-γ mRNA levels by 57% at 24 hours and by 80% at 48 hours compared with those in normoxic cells at 24 hours, while under normoxia PPAR-γ mRNA levels did not differ at 24 and 48 hours. Hypoxia also reduced PPAR-γ protein levels by 20% at 24 hours and by 30% at 48 hours. Treatment TNF-α(10ng/ml) had no influence on a … More mounts of PPAR-γ mRNA or protein.2. Effects of hypoxia on L-fatty acid-binding protein (L-FABP) expression in HPTECs.L-FABP mRNA expression was up-regulated by 3.4-fold after hypoxic treatment for 48 hours.3. PPAR-γ activation by PGJ2 and effects of PGJ2 on expression of MCP-1 and PAI-1 in HPTECs.(1) In HPTECs, a considerable amount of PPAR-g was identified, and treatment with PGJ2 (5 μM) enhanced PPRE-mediated transcriptional activity by 3-fold compared with no treatment. PGJ2 and pioglitazone reduced basal and TNF-α-stimulated MCP-1 expression, which was 30% and 100% PPAR-γ-dependent, respectively. PGJ2 induced further hypoxia-, TNF-α-, and hypoxia plus TNF-α-stimulated PAI-1 expression, which was mediated probably by MAPK and tyrosine kinase, independently of PPAR-γ action. Pioglitazone had no effect on PAI-1 expression.(2) The inhibitory effect of PGJ2 and pioglitazone on MCP-1 expression decreased under hypoxia, while the stimulatory effect of PGJ2 on PAI-1 expression increased under hypoxia. This multiplicity of PGJ2's effects may be explained in part by the PPAR-γ-independent action. Less

1. 缺氧和炎症对培养的人肾近端小管上皮细胞亲脂转录因子表达的影响。(1)利用cDNA阵列系统测定常氧和缺氧条件下hptec亲脂转录因子（PPAR-α、β、γ、RXR-α、β、RAR-α、β、FXR） mRNA表达量。在常氧条件下，所有基因在细胞中均有显著表达。当PPA-α含量为1.0时，RXR、FXR和PPAR-γ的相对mRNA量分别为10.1、5.4和2.1。缺氧使PPA-α mRNA水平降低20%，PPAR-γ mRNA水平降低70%，RX-α mRNA水平降低30%，而缺氧条件下FXR mRNA表达不变。(2)与常氧细胞相比，缺氧使PPAR-γ mRNA在24小时和48小时分别降低57%和80%，而常氧细胞在24和48小时的PPAR-γ mRNA水平没有差异。缺氧也使PPAR-γ蛋白水平在24小时内降低20%，在48小时内降低30%。TNF-α(10ng/ml)对PPAR-γ mRNA或蛋白表达无明显影响。缺氧对hptec中l -脂肪酸结合蛋白（L-FABP）表达的影响。缺氧48小时后，L-FABP mRNA表达上调3.4倍。PGJ2激活PPAR-γ及PGJ2对hptec中MCP-1和PAI-1表达的影响(1)在HPTECs中，发现了相当数量的PPAR-g， PGJ2 （5 μM）处理使ppre介导的转录活性比未处理提高了3倍。PGJ2和吡格列酮降低了基础和TNF-α刺激的MCP-1表达，分别依赖于30%和100% PPAR-γ。PGJ2进一步诱导缺氧-、TNF-α-和缺氧+ TNF-α-刺激PAI-1表达，可能是由MAPK和酪氨酸激酶介导的，不依赖于PPAR-γ的作用。吡格列酮对PAI-1表达无影响。(2)缺氧条件下，PGJ2和吡格列酮对MCP-1表达的抑制作用减弱，而PGJ2对PAI-1表达的刺激作用增强。PGJ2的多重作用可以部分解释为PPAR-γ不依赖的作用。少

项目成果

Increased expression of plasminogen activator inhibitor-1 in hypoxic renal injury and its pathological significance in progression of advanced renal disease.

缺氧性肾损伤中纤溶酶原激活物抑制剂-1 表达增加及其在晚期肾病进展中的病理意义。

• 发表时间: 2005
• 期刊: Rinsho Byori. 53・8
• 作者: Yamamura S;Kishi H;Kondo S;Honda R;Rao SR;Omori M;Tamiya E;Muraguchi A;Kanou et al.;Kimura H
• 通讯作者: Kimura H

Synthetic/secreting and apoptotic phenotypes in renal biopsy tissues from hypertensive nephrosclerosis patients

高血压肾硬化患者肾活检组织的合成/分泌和凋亡表型

• 发表时间: 2006
• 期刊: Hypertension Research 29・8
• 作者: Kimura N;et al.
• 通讯作者: et al.

Hypoxic reduction of peroxisome proliferator-activated receptor-g expression ant its anti-inflammatory effects in human proximal renal tubular cells.

缺氧减少过氧化物酶体增殖物激活受体-g 表达及其在人近端肾小管细胞中的抗炎作用。

• 发表时间: 2006
• 期刊: Therapeutic Research 27・9
• 作者: Harada T;Batsford S;Morioka T;Yao J;Arakawa M;Gejyo F;Oite T;Liming Jin;Li X et al.
• 通讯作者: Li X et al.

Hypoxia reduces the expression and anti-inflammatory effects of peroxisome proliferator-activated receptor-(gamma) in human proximal renal tubular cells.

缺氧会降低人近端肾小管细胞中过氧化物酶体增殖物激活受体（γ）的表达和抗炎作用。

• 发表时间: 2007
• 期刊: Nephrol. Dial. Transplant. 22
• 作者: Li;X.et al.
• 通讯作者: X.et al.

Molecular structures and function of proximal tubular cells.

近端肾小管细胞的分子结构和功能。

• 发表时间: 2006
• 期刊: Nippon Rinsho 64, suppl 2
• 作者: Nephron Experimental Nephrology 99:e38-e45;2005 Yao J;Hiramatsu N;Zhu Y;Morioka T;Takeda M;Oite T;Kitamura M;Kimura H et al.
• 通讯作者: Kimura H et al.