Targeting Bone Morphogenetic Protein 4/Smad1 signaling is a new approach for the treatment of glomerulosclerosis
| Project/Area Number |
16K09613
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 糸球体硬化 / 糖尿病性腎症 / BMP 4 / Fibronectin / Smad1 / 糸球体腎炎 / 病理学 |
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| 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.
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| 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。
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Report
(5 results)
Research Products
(28 results)
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[Journal Article] A Refractory Case of Secondary Membranous Nephropathy Concurrent with IgG4-related Tubulointerstitial Nephritis2018
Author(s)
Arai H, Toda N, Kamimatsuse R, Nishioka K, Endo S, Akiyama S, Maruyama S, Matsubara T, Yokoi H, Yanagita M.
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Journal Title
Internal Medicine
Volume: 57
Issue: 19
Pages: 2873-2877
DOI
NAID
ISSN
0918-2918, 1349-7235
Year and Date
2018-10-01
Related Report
Peer Reviewed / Open Access
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[Journal Article] Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan.2018
Author(s)
Funakoshi T, Horimatsu T, Nakamura M, Shiroshita K, Suyama K, Mukoyama M, Mizukami T, Sakurada T, Baba E, Tsuruya K, Nozaki A, Yahata K, Ozaki Y, Ubara Y, Yasui H, Yoshimoto A, Fukuma S, Kondo N, Matsubara T, Matsubara K, Fukuhara S, Yanagita M, Muto M.
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Journal Title
ESMO Open
Volume: 23
Issue: 2
Pages: e000301-e000301
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Rationale and study design of a clinical trial to assess the effects of LDL apheresis on proteinuria in diabetic patients with severe proteinuria and dyslipidemia.2017
Author(s)
Wada T, Muso E, Maruyama S, Hara A, Furuichi K, Yoshimura K, Miyazaki M, Sato E, Abe M, Shibagaki Y, Narita I, Yokoyama H, Mori N, Yuzawa Y, Matsubara T, Tsukamoto T, Wada J, Ito T, Masutani K, Tsuruya K, Fujimoto S, Tsuda A, Suzuki H, Kasuno K, Terada Y, Nakata T, Iino N, Kobayashi S.
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Journal Title
Clin Exp Nephrol
Volume: -
Issue: 3
Pages: 591-596
DOI
Related Report
Peer Reviewed / Open Access
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