Activin-follistatin system as atarget for the treatment of renal failure

激活素-卵泡抑素系统作为治疗肾衰竭的靶点

• 批准号: 15590842
• 负责人: NOJIMA Yoshihisa
• 金额: $ 1.98万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590842/
• 关键词: activin; follistatin; renal regeneration; renal fibrosis; 線維芽細胞; 形質転換; 筋線維芽細胞; 腎繊維化; 繊維芽細胞; 筋繊維芽細胞

The present study was conducted to examine the involvement of the activin-follistatin system in the fibrotic process of the kidney. Immunoreactive activin A was upregulated in tubular cells in the kidneys with unilateral ureteral obstruction but not in normal and contralateral kidneys. Activin A promoted cell proliferation, enhanced the expression of type I collagen mRNA, and induced the production of α-smooth muscle actin in a rat kidney fibroblast cell line (NRK-49F cells) as well as in primary cultured renal interstitial fibroblasts. In contrast, activin A did not affect the expressions of α-smooth muscle actin and type I collagen in renal epithelial tubular cell lines LLC-PK1, and MDCK. Follistatin, an antagonist of activin A, significantly inhibited cell proliferation in NRK-49F cells. Blockade of activin signaling by overexpression of truncated type II activin receptor, which lacked the intracellular kinase domain, decreased cell proliferation and reduced the expression level of type I collagen mRNA in NRK-49F cells. The expression of activin A was induced by TGF-^β1 or activin A itself. Induction of type I collagen expression by TGF-^β1 was reduced by follistatin or by overexpression of truncated type II activin receptor. These results suggest that activin A produced by tubular cells acts as a paracrine factor that activates renal interstitial fibroblasts during the fibrotic processes of the kidney.

本研究旨在探讨激活素-卵泡抑素系统在肾脏纤维化过程中的作用。免疫反应性激活素A在单侧输尿管梗阻的肾小管细胞中上调，但在正常和对侧肾脏中未上调。激活素A促进细胞增殖，增强I型胶原mRNA的表达，并诱导大鼠肾成纤维细胞系（NRK-49 F细胞）以及原代培养的肾间质成纤维细胞中α-平滑肌肌动蛋白的产生。相反，激活素A不影响肾小管上皮细胞株LLC-PK 1和MDCK中α-平滑肌肌动蛋白和I型胶原的表达。激活素A的拮抗剂卵泡抑素可显著抑制NRK-49 F细胞的增殖。通过过表达缺乏胞内激酶结构域的截短型II型激活素受体阻断激活素信号传导，降低NRK-49 F细胞中的细胞增殖并降低I型胶原mRNA的表达水平。激活素A的表达由TGF-β1或激活素A本身诱导。卵泡抑素或截短型II型激活素受体的过表达可降低TGF-β1诱导的I型胶原表达。这些结果表明，肾小管细胞产生的激活素A作为旁分泌因子，在肾脏纤维化过程中激活肾间质成纤维细胞。

项目成果

Akito Maeshima 他: "Identification of Renal Progenitor-Like Tubular Cells that Participate in the Regeneration Processes of the Kidney"Journal of American Society of Nephrology. 14. 3138-3146 (2003)

Akito Maeshima 等人：“参与肾脏再生过程的肾祖样管状细胞的鉴定”美国肾病学会杂志 14. 3138-3146 (2003)。

Involvement of Renal Progenitor-like Tubular Cells in Epithelial-to-Mesenchymal Transition in Fibrotic Rat Kidneys

肾祖细胞样管状细胞参与纤维化大鼠肾脏上皮间质转化

• 期刊: J Am Soc Nephrol (in press)
• 作者: Maeshima A;Yamashita S;Nojima Y;Yamashita S
• 通讯作者: Yamashita S

Activin A is a potent activator for renal interstitial fibroblasts

Activin A 是肾间质成纤维细胞的有效激活剂

• 发表时间: 2004
• 期刊: J Am Soc Nephrol 15
• 作者: Hirohisa;Toga.;長内和弘;Yamashita S
• 通讯作者: Yamashita S

Shin Yamashita 他: "Activin A Is a Potent Activator of Renal Interstitial Fibroblasts"Journal of American Society of Nephrology. 15. 91-101 (2004)

Shin Yamashita 等人：“激活素 A 是肾间质成纤维细胞的有效激活剂”，美国肾病学会杂志 15. 91-101 (2004)。

Activin A is a potent activator of renal interstitial fibroblasts.

• DOI: 10.1097/01.asn.0000103225.68136.e6
• 发表时间: 2004
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Shin Yamashita;A. Maeshima;I. Kojima;Y. Nojima