Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases

Vera Eremina, Manish Sood, Jody Haigh, András Nagy, Ginette Lajoie, Napoleone Ferrara, Hans Peter Gerber, Yamato Kikkawa, Jeffrey H. Miner, Susan E. Quaggin

Research output: Contribution to journalArticle

952 Scopus citations

Abstract

Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.

Original languageEnglish
Pages (from-to)707-716
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number5
DOIs
StatePublished - Mar 2003

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    Eremina, V., Sood, M., Haigh, J., Nagy, A., Lajoie, G., Ferrara, N., Gerber, H. P., Kikkawa, Y., Miner, J. H., & Quaggin, S. E. (2003). Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. Journal of Clinical Investigation, 111(5), 707-716. https://doi.org/10.1172/JCI17423