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Mouse Models of Glomerulogenesis and Glomerular Disease
Author(s) -
Quaggin Susan E.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a137
Subject(s) - podocyte , glomerulus , microbiology and biotechnology , glomerular basement membrane , biology , basement membrane , vascular endothelial growth factor , kidney , kidney development , renal glomerulus , medicine , endocrinology , glomerulonephritis , gene , cancer research , vegf receptors , proteinuria , genetics , embryonic stem cell
Each human kidney contains approximately 1 million glomeruli that filter the blood, removing excess fluid and small solutes from the body. Glomeruli are formed from metanephric mesenchymal cells that have been induced by adjacent ureteric bud epithelium. In the mature kidney, the glomerular filtration barrier (GFB) consists of highly specialized glomerular epithelial cells (podocytes), fenestrated endothelial cells and an intervening glomerular basement membrane. Over the past two decades, genetic targeting in mice has provided great insight into the function of many genes in glomerular development and disease. In our lab, we have identified a transcription factor known as Tcf21 that is expressed in presumptive and mature podocytes. Through standard gene targeting, we showed that Tcf21 is required for terminal differentiation of podocytes, ingrowth of glomerular capillaries and formation of a functional GFB. We have also generated a number of genetic tools that enable temporally and spatially controlled deletion or over‐expression of genes in specific cell compartments of the glomerulus. Using this approach, we have shown that crosstalk between the podocyte and glomerular endothelium is critical for development and maintenance of the GFB. One major player in these interactions is the angiogenic factor, VEGF‐A. During development there is exquisite dosage sensitivity to this factor, as increasing reductions in VEGF‐A produced by the podocyte lead to more severe defects in the endothelial compartment. Conversely, upregulation of the major VEGF‐164 isoform in developing or mature glomeruli leads to marked and rapid changes in glomerular permeability. Podocyte‐selective stabilization of the hypoxia inducible factors that regulate VEGF‐A leads to an explosive onset of crescentic glomerular disease, podocyte proliferation and death due to renal failure. Taken together, these results demonstrate the power of mouse genetics to study glomerular biology, emphasize that podocytes function as vasculature support cells and provide preclinical models for renal disease.