Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 May 15;99(10):2351–2357. doi: 10.1172/JCI119416

Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis.

Y Kitamoto 1, H Tokunaga 1, K Tomita 1
PMCID: PMC508073  PMID: 9153276

Abstract

Homeostasis of body fluid is maintained by the kidneys, which contain two million glomeruli for blood filtration. A glomerulus is formed by growth of Bowman's capsule harmonized with a capillary during kidney development. The vascular endothelial growth factor (VEGF) is an essential angiogenic cytokine, and VEGF deficiency is known to be fatal in mice in early embryonic stages. As secretions of VEGF from cultured kidneys vary according to developmental stages, the role of VEGF in kidney development was studied in vivo by blocking the endogenous VEGF activity with antibody in newborn mice, in which most organs are already developed but kidneys are still developing. The antibody-treated animals showed normal growth but systemic edema. Vessel formation in the superficial renal cortex was disturbed, nephrogenic areas were diminished, and the number of developing nephrons decreased significantly. Many abnormal glomeruli, lacking capillary tufts, were observed in the antibody-treated mice, and VEGF expression in their Bowman's capsule showed a compensatory increase. These results suggest that VEGF mediates communication between the Bowman's capsule and capillary endothelial cells for developing a glomerulus as well as promoting nephrogenesis. In conclusion, VEGF is likely to be an essential molecule for kidney development, and especially for glomerulogenesis.

Full Text

The Full Text of this article is available as a PDF (922.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrahamson D. R. Origin of the glomerular basement membrane visualized after in vivo labeling of laminin in newborn rat kidneys. J Cell Biol. 1985 Jun;100(6):1988–2000. doi: 10.1083/jcb.100.6.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abrahamson D. R. Structure and development of the glomerular capillary wall and basement membrane. Am J Physiol. 1987 Nov;253(5 Pt 2):F783–F794. doi: 10.1152/ajprenal.1987.253.5.F783. [DOI] [PubMed] [Google Scholar]
  3. Bacic M., Edwards N. A., Merrill M. J. Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors. 1995;12(1):11–15. doi: 10.3109/08977199509003209. [DOI] [PubMed] [Google Scholar]
  4. Bernstein J., Cheng F., Roszka J. Glomerular differentiation in metanephric culture. Lab Invest. 1981 Aug;45(2):183–190. [PubMed] [Google Scholar]
  5. Breier G., Albrecht U., Sterrer S., Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992 Feb;114(2):521–532. doi: 10.1242/dev.114.2.521. [DOI] [PubMed] [Google Scholar]
  6. Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Eberhardt C. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435–439. doi: 10.1038/380435a0. [DOI] [PubMed] [Google Scholar]
  7. Ferrara N., Carver-Moore K., Chen H., Dowd M., Lu L., O'Shea K. S., Powell-Braxton L., Hillan K. J., Moore M. W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996 Apr 4;380(6573):439–442. doi: 10.1038/380439a0. [DOI] [PubMed] [Google Scholar]
  8. Fong G. H., Rossant J., Gertsenstein M., Breitman M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995 Jul 6;376(6535):66–70. doi: 10.1038/376066a0. [DOI] [PubMed] [Google Scholar]
  9. Hanatani M., Tanaka Y., Kondo S., Ohmori I., Suzuki H. Sensitive chemiluminescence enzyme immunoassay for vascular endothelial growth factor/vascular permeability factor in human serum. Biosci Biotechnol Biochem. 1995 Oct;59(10):1958–1959. doi: 10.1271/bbb.59.1958. [DOI] [PubMed] [Google Scholar]
  10. Kaipainen A., Korhonen J., Pajusola K., Aprelikova O., Persico M. G., Terman B. I., Alitalo K. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med. 1993 Dec 1;178(6):2077–2088. doi: 10.1084/jem.178.6.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Levéen P., Pekny M., Gebre-Medhin S., Swolin B., Larsson E., Betsholtz C. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 1994 Aug 15;8(16):1875–1887. doi: 10.1101/gad.8.16.1875. [DOI] [PubMed] [Google Scholar]
  12. Perantoni A. O., Dove L. F., Karavanova I. Basic fibroblast growth factor can mediate the early inductive events in renal development. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4696–4700. doi: 10.1073/pnas.92.10.4696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Peters K. G., De Vries C., Williams L. T. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8915–8919. doi: 10.1073/pnas.90.19.8915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ritvos O., Tuuri T., Erämaa M., Sainio K., Hildén K., Saxén L., Gilbert S. F. Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse. Mech Dev. 1995 Apr;50(2-3):229–245. doi: 10.1016/0925-4773(94)00342-k. [DOI] [PubMed] [Google Scholar]
  15. Rogers S. A., Ryan G., Hammerman M. R. Insulin-like growth factors I and II are produced in the metanephros and are required for growth and development in vitro. J Cell Biol. 1991 Jun;113(6):1447–1453. doi: 10.1083/jcb.113.6.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Santos O. F., Nigam S. K. HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-beta. Dev Biol. 1993 Dec;160(2):293–302. doi: 10.1006/dbio.1993.1308. [DOI] [PubMed] [Google Scholar]
  17. Sariola H., Saarma M., Sainio K., Arumäe U., Palgi J., Vaahtokari A., Thesleff I., Karavanov A. Dependence of kidney morphogenesis on the expression of nerve growth factor receptor. Science. 1991 Oct 25;254(5031):571–573. doi: 10.1126/science.1658930. [DOI] [PubMed] [Google Scholar]
  18. Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
  19. Shalaby F., Rossant J., Yamaguchi T. P., Gertsenstein M., Wu X. F., Breitman M. L., Schuh A. C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995 Jul 6;376(6535):62–66. doi: 10.1038/376062a0. [DOI] [PubMed] [Google Scholar]
  20. Shifren J. L., Doldi N., Ferrara N., Mesiano S., Jaffe R. B. In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and myocytes, but not vascular endothelium: implications for mode of action. J Clin Endocrinol Metab. 1994 Jul;79(1):316–322. doi: 10.1210/jcem.79.1.8027247. [DOI] [PubMed] [Google Scholar]
  21. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  22. Simon M., Gröne H. J., Jöhren O., Kullmer J., Plate K. H., Risau W., Fuchs E. Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Physiol. 1995 Feb;268(2 Pt 2):F240–F250. doi: 10.1152/ajprenal.1995.268.2.F240. [DOI] [PubMed] [Google Scholar]
  23. Soriano P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 1994 Aug 15;8(16):1888–1896. doi: 10.1101/gad.8.16.1888. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES