Targeting Bone Morphogenetic Protein 4/Smad1 signaling is a new approach for the treatment of glomerulosclerosis

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K09613
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: Takeshi Matsubara 京都大学, 医学研究科, 講師 (90422964)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 糸球体硬化

Outline of Final Research Achievements

Glomerulosclerosis is common final pathological features, characterized by the accumulation of extracellular matrix, of which the main component is α1/α2 type IV collagen (Col4α1/α2). Recently, we identified Smad1 as a direct regulator of Col4α1/α2, and showed that diabetic mice treated with a neutralizing antibody against BMP4, upstream factor of Smad1, exhibit less mesangial expansion. However, They did not show any improvement of albuminuria. Therefore, we checked molecules involved in albuminuria and found that glomerular expression of fibronectin was increased with the treatment of this antibody. We also generated conditional deletion of Smad1 (Smad1-CKO). Mesangial matrix expansion was ameliorated in Smad1-CKO mice after the induction of nephritis. Furthermore, after 36 weeks, some Smad1-CKO mice showed glomerular endotheliosis and mesangiolysis. Thus, Smad1 plays a key role for matrix expansion, and possible role for the homeostasis of glomerular endothelial cells.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

本研究結果により、BMP4-Smad1シグナルは糸球体硬化の治療標的となることが判明したが、我々のBMP4中和抗体投与では、糸球体Fibronectin沈着と蛋白尿の増加という有害事象が発生した。In vitroで検証により、この機序は本抗体の持つBMP7抑制作用と考えられた。しかし、BMP4の受容体であるALK3の阻害薬dorsomorphinを用いた結果から、BMP4シグナルの創薬応用として、ALK3が新たな治療標的となる可能性も示唆された。さらに、誘導型Smad1欠損マウスの検討から、Smad1が糸球体細胞外基質の制御のみならず、糸球体内皮細胞の恒常性にも関与している可能性が示唆された。