Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases
Vera Eremina, … , Jeffrey H. Miner, Susan E. Quaggin
Vera Eremina, … , Jeffrey H. Miner, Susan E. Quaggin
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):707-716. https://doi.org/10.1172/JCI17423.
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Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases

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.

Authors

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

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Figure 4

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Digoxigenin-labeled in situ analysis of wild-type and mutant glomeruli. ...
Digoxigenin-labeled in situ analysis of wild-type and mutant glomeruli. (a–c) Capillary loop–stage glomeruli from a newborn VEGF-loxP–/–,Neph-Cre+/– control mouse demonstrate expression of VEGF-A and WT1 in podocytes, while VSMA is expressed in mesangial cells, which are found inside the glomerulus and are required to support the capillary structure. (d–f) At birth (P0), capillary loop–stage glomeruli from a heterozygous VEGF-loxP+/–,Neph-Cre+/– mouse demonstrate normal levels of expression of WT1 and VSMA, while VEGF expression is consistently reduced at the mRNA level compared with the wild-type controls. (g–i) By 9 weeks of age, the heterozygous VEGF mice are clinically unwell. At this time, most glomeruli demonstrate a complete absence of markers of podocyte differentiation (i.e., no VEGF or WT1; both are absent). In h, a single WT1-positive cell can be identified (arrow). (i) VSMA is not usually present in glomeruli at 9 weeks; however, occasional VSMA-positive cells can also be identified and likely represent “activated” mesangial cells (arrow). (j–l) In the null VEGF-loxP+/+,Neph-Cre+/– glomeruli at birth, no VEGF is seen in glomeruli as predicted due to podocyte-specific excision of both VEGF alleles. WT1 is present in differentiated podocytes. In contrast, VSMA is absent, demonstrating a defect in migration and/or differentiation of mesangial cells into the glomerulus. (m–o) In the nephrin–VEGF-164 mouse, both VEGF and WT1 are expressed in podocytes present within collapsed glomeruli. VEGF is markedly upregulated. In addition, VSMA and mesangial cells are present but appear to surround the collapsed glomerulus in a crescent shape. Magnification: ×350.