Forced expression of vascular endothelial growth factor-A in podocytes decreases mesangial cell numbers and attenuates endothelial cell differentiation in the mouse glomerulus

被引:12
作者
Suyama, Masahiro [1 ]
Miyazaki, Yoichi [1 ]
Matsusaka, Taiji [2 ]
Sugano, Naoki [1 ]
Ueda, Hiroyuki [1 ]
Kawamura, Tetsuya [1 ]
Ogura, Makoto [1 ]
Yokoo, Takashi [1 ]
机构
[1] Jikei Univ, Sch Med, Div Nephrol & Hypertens,Dept Internal Med, Minato Ku, 3-25-8 Nishi Shinbashi, Tokyo 1058461, Japan
[2] Tokai Univ, Dept Internal Med, Sch Med, 143 Shimokasuya, Isehara, Kanagawa 2591193, Japan
关键词
Glomerular development; Inducible transgenic mice; Plasmalemmal vesicle-associated protein-1; Platelet-derived growth factor; PDGF-B; VEGF-A; PERICYTE; MICE; OVEREXPRESSION; FENESTRATIONS; DEFICIENT;
D O I
10.1007/s10157-017-1450-5
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Glomerular podocyte-derived vascular endothelial growth factor (VEGF) is indispensable for the migration and proliferation of glomerular endothelial cells. In contrast, podocyte-specific Vegf overexpression leads to the collapse of glomerular tufts; however, the mechanisms underlying this outcome have not yet been reported. To further clarify the effects of elevated levels of Vegf expression on glomerular cells, we established a dual transgenic mouse line in which Vegf was exclusively and inducibly expressed in podocytes under the control of the "Tet-on system" (Podocin-rtTA/TetO-Vegf164 mice). Macroscopic and microscopic examination of Podocin-rtTA/TetO-Vegf164 animals following Vegf induction identified the presence of prominent red bloody spots. In addition, the endothelial cell number was increased along with enlargement of the subendothelial spaces. We also observed impaired endothelial fenestrations and aberrant plasmalemmal vesicle-associated protein-1 (PV-1) expression. In contrast, the mesangial cell number markedly decreased, resulting in a glomerular tuft intussusceptive splitting defect. Furthermore, whereas platelet-derived growth factor-B (PDGF-B) expression in the glomerular cells of Podocin-rtTA/TetO-Vegf164 mice was not decreased, phospho-PDGF receptor immunoreactivity in the mesangial cells was significantly decreased when compared to wild-type animals. Taken together, the results of this study indicated that the upregulation of podocyte VEGF decreased the number of mesangial cells, likely owing to inhibition of PDGF-B-mediated signaling.
引用
收藏
页码:266 / 274
页数:9
相关论文
共 26 条
[1]  
Benjamin LE, 1998, DEVELOPMENT, V125, P1591
[2]   Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development [J].
Boyle, Scott C. ;
Liu, Zhenyi ;
Kopan, Raphael .
DEVELOPMENT, 2014, 141 (02) :346-354
[3]   Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele [J].
Carmeliet, P ;
Ferreira, V ;
Breier, G ;
Pollefeyt, S ;
Kieckens, L ;
Gertsenstein, M ;
Fahrig, M ;
Vandenhoeck, A ;
Harpal, K ;
Eberhardt, C ;
Declercq, C ;
Pawling, J ;
Moons, L ;
Collen, D ;
Risau, W ;
Nagy, A .
NATURE, 1996, 380 (6573) :435-439
[4]   Endothelial cells and VEGF in vascular development [J].
Coultas, L ;
Chawengsaksophak, K ;
Rossant, J .
NATURE, 2005, 438 (7070) :937-945
[5]   Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases [J].
Eremina, V ;
Sood, M ;
Haigh, J ;
Nagy, A ;
Lajoie, G ;
Ferrara, N ;
Gerber, HP ;
Kikkawa, Y ;
Miner, JH ;
Quaggin, SE .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (05) :707-716
[6]   Vascular endothelial growth factor induces endothelial fenestrations in vitro [J].
Esser, S ;
Wolburg, K ;
Wolburg, H ;
Breier, G ;
Kurzchalia, T ;
Risau, W .
JOURNAL OF CELL BIOLOGY, 1998, 140 (04) :947-959
[7]   Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells [J].
Frank, S ;
Stallmeyer, B ;
Kämpfer, H ;
Schaffner, C ;
Pfeilschifter, J .
BIOCHEMICAL JOURNAL, 1999, 338 :367-374
[8]   A role for VEGF as a negative regulator of pericyte function and vessel maturation [J].
Greenberg, Joshua I. ;
Shields, David J. ;
Barillas, Samuel G. ;
Acevedo, Lisette M. ;
Murphy, Eric ;
Huang, Jianhua ;
Scheppke, Lea ;
Stockmann, Christian ;
Johnson, Randall S. ;
Angle, Niren ;
Cheresh, David A. .
NATURE, 2008, 456 (7223) :809-U101
[9]   Glomerular Endothelial Cells Form Diaphragms during Development and Pathologic Conditions [J].
Ichimura, Koichiro ;
Stan, Radu V. ;
Kurihara, Hidetake ;
Sakai, Tatsuo .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2008, 19 (08) :1463-1471
[10]   Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin α5 in the glomerular basement membrane [J].
Kikkawa, Y ;
Virtanen, I ;
Miner, JH .
JOURNAL OF CELL BIOLOGY, 2003, 161 (01) :187-196