Physiological function of ageing suppression gene klotho and its role in development of adult disease

衰老抑制基因klotho的生理功能及其在成人疾病发生发展中的作用

• 批准号: 09470159
• 负责人: NAGAI Ryozo
• 金额: $ 9.73万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470159/
• 关键词: AGING; ENDOTHELIUM; NITRIC OXIDE; PARABIOSIS; HUMORAL FACTOR; HYPERTENSION; KLOTHO; 動脈硬化; 腎不全; 高血圧; 老化抑制遺伝子; aging; klotho

Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of Klotho mouse or the pathophysiological role of klotho gene product as a circulating factor is available. We demonstrate that the vasodilator response of aorta and arterioles to acetylcholine was significantly attenuated in homozygous klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous klotho mice resulted in restoration of endothelial function in heterozygous Klotho mice. Nitric oxide metabolites (NO2- and NO3-) in urine are significantly lower in heterozygous Klotho mice (142 *16nmol/day) than wild-type mice (241* 28nmol/day). We also showed that kiotho mRNA expression is significantly decreased in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats developing hypertension, obesity, insulin resistance, and hypertriglyceridemia.We conclude that the Klotho protein protects against the cardiovascular dysfunction through endothelium-derived NO production by humoral pathways.

由衰老引起的动脉硬化被认为是心血管疾病的重要危险因素。我们最近建立了Klotho小鼠，它会导致包括动脉硬化在内的与年龄相关的疾病。然而，关于Klotho小鼠的内皮功能或Klotho基因产物作为循环因子的病理生理作用的信息尚不清楚。我们证明，与野生型小鼠相比，纯合子Klotho小鼠的主动脉和小动脉对乙酰胆碱的血管扩张反应显著减弱。野生型Klotho小鼠和杂合子Klotho小鼠之间的共生导致杂合子Klotho小鼠内皮功能的恢复。Klotho杂合子小鼠的尿中一氧化氮代谢产物(NO2-和NO3-)显著低于野生型小鼠(241*28nmo1/天)。我们还发现，在自发性高血压大鼠、脱氧皮质酮醋酸酯(DOCA)盐性高血压大鼠和大冢Long-Evans Tokushima Fatty(OLETF)大鼠发展为高血压、肥胖、胰岛素抵抗和高甘油三酯血症时，Kisoo基因的mRNA表达显著降低。我们得出结论，Klotho蛋白通过体液途径产生内皮来源的NO来保护心血管功能障碍。

项目成果

Aizawa H,Saito Y,Nakamura T,Inoue M,Imanari T,Ohyama Y,Matsumura Y,Masuda H,Oba S,Mise N,Kimura K,Hasegawa A,Kurabayashi M,Kuro-o M,Nabeshima Y,Nagai R.: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem

相泽 H、斋藤 Y、中村 T、井上 M、今成 T、大山 Y、松村 Y、增田 H、Oba S、Mise N、木村 K、长谷川 A、仓林 M、黑男 M、锅岛 Y、永井 R。

Shiraki-Iida T., Aizawa H., Matsumura Y., Sekine S., Iida A., Anazawa H., Nagai R., Kuro-o M., Nabeshima Y.: "Structure of the mouse Klotho gene and its two transcripts encoding membrane and secreted protein" FEBS Lett.424 (1-2). 6-10 (1998)

Shiraki-Iida T.、Aizawa H.、Matsumura Y.、Sekine S.、Iida A.、Anazawa H.、Nagai R.、Kuro-o M.、Nabeshima Y.：“小鼠 Klotho 基因及其两个基因的结构

Matsumura Y.et al: "Identification of the human Klotho gene and its two transcripts encoding membrane and secreted Klotho protein." Biochem. Byophys. Res. Commun.243・3. 626-630 (1998)

Matsumura Y. 等人：“人类 Klotho 基因及其编码膜和分泌型 Klotho 蛋白的鉴定。Biochem.243·3”。

Ohyama Y.et al: "Molecular cloning of rat Klotho cDNA : markedly decreased expression of Klotho by acute inflammatory stress." Biochem.Biophys.Res.Commun.251・3. 920-925 (1998)

Ohyama Y.等人：“大鼠Klotho cDNA的分子克隆：急性炎症应激显着降低了Klotho的表达。”Biochem.Biophys.Res.Commun.251·3（1998）。