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 1

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Expression and genomic targeting of VEGF-A within the glomerular filtrat...
Expression and genomic targeting of VEGF-A within the glomerular filtration barrier. (a) Transmission electron micrograph of the glomerular filtration barrier that consists of podocytes (po) and their specialized foot processes (fp), fenestrated endothelium (en), and intervening GBM. VEGF-A is produced in the podocyte; the VEGF receptors Flk1 and Flt1 are expressed in the adjacent endothelial cells. (b) Development of the glomerular filtration barrier. In the S-shape stage, podocyte precursors (po) express VEGF-A. Endothelial cells (en) that express the VEGF receptors migrate into the vascular (Vasc) cleft and differentiate in direct apposition to podocytes. In the mature glomerulus, the fenestrated endothelial capillary loops (cap) remain in intimate contact with the VEGF-expressing podocytes (po). Mesangial cells (me) provide support to the capillary tuft. Urine is formed as blood (bl) is filtered from the capillaries, across the GBM, and through slit diaphragms that connect adjacent podocyte foot processes (fp). (c) Scheme to generate heterozygous and homozygous podocyte-specific VEGF knockout mice. Triangles are 34 bp loxP sites. (d) The Cre recombinase transgene was identified as a 300 bp PCR product. The floxed VEGF allele measures 140 bp by PCR analysis, whereas the wild-type allele measures 100 bp. MW, molecular weight markers. (e) Transgenic construct used to overexpress the 164-isoform of VEGF. pA, poly(A). (f) Presence of the transgenic VEGF-164 gene was identified as a 1.3-kb band (*) by Southern blot analysis. (g) Dot blot analysis of transgene copy number. The transgenic founder mice (164) demonstrated a 30-fold increase in copy number compared with the wild type.