Protective Role of the Natriuretic Peptide System in Tissue Injury and Remodeling

利钠肽系统在组织损伤和重塑中的保护作用

• 批准号: 13671152
• 负责人: MUKOYAMA Masashi
• 金额: $ 0.9万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671152/
• 关键词: Natriuretic peptide; Transgenic mouse; Glomerulonephritis; Diabetic nephropathy; Renal fibrosis; Mesangial cell; Endothelial protection; Vascular regeneration; 腎間質線維化; 細胞外基質; 腎保護

In prder to explore the rote of natriuretic peptides, with potent diuretic and vasorelaxing properties, in tissue injury and remodeling, we investigated the effect of chronic excess of brain natriuretic peptide (BNP) in transgenic mice on renal injuries using various nephropathy modelsIn a model of anti-glomerular-basement-membrane antibody glomerulonephritis (GN), control nontransgenic mice developed progressive GN with heavy prateinuria (21 times of baseline level) and severe glomerular/tubulointerstitial damage at 8-12 weeks. In contrast, BNP-transgenic mice (BNP-Tg) showed only minor and transient proteinuria with no apparent tissue damage. Gene expression of transforming growth factorβ (TGF-β) and monocyte chemoattractant protein-1 (MCP-1) as well as the activation of ERK/MAP kinase within renal tissues was much reduced in BNP-Tg, suggesting that these worked together to ameliorate renal injuriesIn a model of renal fibrosis with unilateral ureteral obstruction (UUO), interstitial … More fibrosis was significantly ameliorated in BNP-Tg as compared with control nontransgenic mice. TGF-β expresstan was much reduced in BNP-Tg. Subsequent analysis revealed that the blood fbw in the renal peritubular capillary was significantly maintained in BNP-Tg, suggesting that such mechanisms of vascular protection may act against the progression of fibrotic processesIn a model of diabetic nephropathy, control mice developed significant proteinuria with masangial expansion 16 weeks after the onset of streptozotocin-induced diabetes. These changes were significantly milder in BNP-Tg. BNP inhibited the mesangial up regulation of TGF-β in vivo and in vitro, suggesting that this may provide a common key mechanism of renoprotectionThese results indicate that natriuretic peptides potentially exert renoprotective effects by counteracting the fibrogenic stimuli such as TGF-βand MCP-1, suggesting that the activation of the natriuretic peptide system should be clinically applicable against various nephropathies Less

为了探索具有强效利尿和血管舒张特性的利尿钠肽在组织损伤和重塑中的作用，我们使用各种肾病模型研究了转基因小鼠中长期过量的脑钠尿肽（BNP）对肾损伤的影响。 肾小球肾炎 (GN)，对照非转基因小鼠在 8-12 周时出现进行性 GN，伴有严重蛋白尿（基线水平的 21 倍）和严重肾小球/肾小管间质损伤。相比之下，BNP 转基因小鼠 (BNP-Tg) 仅表现出轻微且短暂的蛋白尿，没有明显的组织损伤。 BNP-Tg 中肾组织内转化生长因子 β (TGF-β) 和单核细胞趋化蛋白 1 (MCP-1) 的基因表达以及 ERK/MAP 激酶的激活大大降低，表明这些共同作用可改善肾损伤。在单侧输尿管梗阻 (UUO) 肾纤维化模型中，间质纤维化显着减少 与对照非转基因小鼠相比，BNP-Tg 有所改善。 BNP-Tg 中的 TGF-β 表达大大减少。随后的分析显示，肾小管周围毛细血管中的血液 fbw 显着维持在 BNP-Tg 中，这表明这种血管保护机制可能会对抗纤维化过程的进展。在糖尿病肾病模型中，对照小鼠在链脲佐菌素诱导的糖尿病发病后 16 周出现明显的蛋白尿，并伴有马囊扩张。 BNP-Tg 中的这些变化明显较轻。 BNP在体内和体外抑制系膜上调的TGF-β，表明这可能提供了共同的肾脏保护关键机制。这些结果表明，利钠肽可能通过对抗TGF-β和MCP-1等纤维化刺激来发挥肾脏保护作用，这表明利钠肽系统的激活应该在临床上适用于对抗肾损伤。 各种肾病较少

项目成果

Akihiro Yoshimoto, et al.: "Plasma ghrelin and desacyl ghrelin concentrations in renal failure"Journal of die American Society of Nephrology. 13 (11). 2748-2752 (2002)

Akihiro Yoshimoto 等人：“肾衰竭中的血浆生长素释放肽和去酰基生长素释放肽浓度”美国肾病学会杂志。

Masahisa Goto: "Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertgpsive rats"Hypertension Research. 25・1. 125-133 (2002)

后藤正久：“血管紧张素II 2型受体在自发性高血压大鼠的肾和系膜细胞中的表达和作用”高血压研究25・1（2002）。

Takayoshi Suganami: "Overexpression of brain natriuretic peptide in mice ameliorates immunemediated renal injury"Journal of the American Society of Nephrology. 12(12). 2652-2663 (2001)

Takayoshi Suganami：“小鼠脑钠尿肽的过度表达可改善免疫介导的肾损伤”美国肾脏病学会杂志。

Masayo Nakagawa, et al.: "Monoclonal antibody against brain natriuretic peptide and characterization of brain natriuretic peptide-transgenic mice"Journal of Hypertension. 19 (3). 475-483 (2001)

Masayo Nakakawa等人：“抗脑钠尿肽的单克隆抗体和脑钠尿肽转基因小鼠的特征”高血压杂志。

Hideki Yokoi: "Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis"American Journal of Physiology Renal Physiology. 282(5). F933-F942 (2002)

横井秀树：“结缔组织生长因子在纤连蛋白表达和肾小管间质纤维化中的作用”美国生理学肾生理学杂志。