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 6

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Mice that overexpress the 164 isoform of VEGF-A in their podocytes devel...
Mice that overexpress the 164 isoform of VEGF-A in their podocytes develop collapsing glomerulopathy. (a and b) Whole-mount images of VEGF-overexpressing kidneys at 5 days. The kidneys demonstrate many surface hemorrhages. (c) A glomerulus stained with H&E from a wild-type littermate. (d) A glomerulus from a transgenic VEGF-overexpressing mouse demonstrates global collapse of the capillary tuft toward the vascular pole of the glomerulus. A single patent capillary loop that appears dilated is identified (Cap). In addition, Bowman’s space (BS) is enlarged. (e) A 5-day-old wild-type glomerulus is stained with silver methenamine that recognizes basement membranes (black). Note the intricate pattern of GBM that lines the capillary loops between endothelial cells and podocytes. (f) In contrast, a transgenic glomerulus demonstrates complete collapse of the capillary network. (g) A high-power view of the capillary loops (Cap) in a wild-type glomerulus. (h) In contrast, the few patent capillary loops identified at 5 days of age in the transgenic mice demonstrate increased diameter and multiple endothelial cell nuclei (arrowheads). (i) A wild-type capillary loop at 5 days of age. Note the fenestrated endothelium (arrow). Although a portion of an endothelial cell body is identified (arrowhead), glomerular endothelial cell nuclei are difficult to find on EM sections. (j) In a transgenic patent capillary loop at 5 days of age, three endothelial cell nuclei are easily identified (arrowheads). Magnification in a and b: ×60; in c–f: ×225; in g and h: ×1,000. In i, bar = 2,000 nm; in j, bar = 5,000 nm.