期刊
KIDNEY INTERNATIONAL
卷 88, 期 3, 页码 479-489出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.103
关键词
CD26; CD29; EndMT; Flt1; Flk1; smad3
资金
- Japan Society for Promotion of Science [23790381, 25282028, 25670414]
- Japan Research Foundation for Clinical Pharmacology
- Kanazawa Medical University [C2011-4, C2012-1, S2011-1, S2012-5]
- Grant for Precursory Alumni Research(B) from Kanazawa Medical University [PR2012-10]
- Daiichi-Sankyo Foundation of Life Science
- Ono Medical Research Foundation
- NOVARTIS Foundation (Japan) for Promotion of Science
- Takeda Science Foundation
- Banyu Foundation
- Japanese Government MEXT (Ministry of Education, Culture, Sports, Science, and Technology) Fellowship Program
- Grants-in-Aid for Scientific Research [23790381, 24790329, 25282028, 25670414] Funding Source: KAKEN
Integrin beta 1 and dipeptidyl peptidase (DPP)-4 play roles in endothelial cell biology. Vascular endothelial growth factor (VEGF)-A inhibits endothelial-to-mesenchymal transition (EndMT) through VEGF-R2, but through VEGF-R1 promotes EndMT by reducing the bioavallability of VEGF-A. Here we tested whether DPP-4-integrin beta 1 interactions have a role in EndMT in the renal fibrosis of diabetic nephropathy. In streptozotocin-induced fibrotic kidneys in diabetic CD-1 mice, levels of endothelial DPP-4, integrin beta 1, and phospho-integrin beta 1 were all higher and associated with plasma cystatin C elevation. The DPP-4 inhibitor linagliptin ameliorated kidney fibrosis, reduced plasma cystatin C levels, and suppressed endothelial levels of DPP-4, integrin beta 1, and phospho-integrin beta 1. In cultured endothelial cells, DPP-4 and integrin beta 1 physically interacted. Suppression of DPP-4 by siRNA was associated with suppression of integrin beta 1 and vice versa. Knockdown of either integrin beta 1 or DPP-4 resulted in the silencing of TGF-beta 2-induced TGF-beta receptor heterodimer formation, smad3 phosphorylation, and EndMT. DPP-4 negatively regulated endothelial viability signaling by VEGF-R2 suppression and VEGF-R1 induction in endothelial cells. Thus, DPP-4 and integrin beta 1 interactions regulate key endothelial cell signal transduction in both physiological and pathological conditions including EndMT. Hence, inhibiting DPP-4 may be a therapeutic target for treating kidney fibrosis in diabetes.
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