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Abstract
The kidney ultrafiltration barrier is formed of endothelial cells, the glomerular basement membrane and podocytes. Podocytes have a central role in normal physiology and disease pathogenesis of the glomerulus. Signaling through epidermal growth factor receptor (EGFR) in podocytes mediates development of many glomerular disease processes. In this work, we have identified zinc finger FYVE-type containing 28 (ZFYVE28) as a novel highly podocyte-enriched gene. We localize ZFYVE28 in podocyte foot processes in adult kidney. During glomerulogenesis, Zfyve28 is first expressed at the early capillary loop glomerulus. In cultured podocytes, we show that overexpression of ZFYVE28 promotes EGF-signaling, possibly by up-regulating EGFR expression and by modulating its localization. To study the role of ZFYVE28 in vivo, we generated both conventional and podocyte-specific knockout mouse lines. Kidneys developed normally in ZFYVE28-deficient mice. In adult mice, the absence of ZFYVE28 did not affect the maintenance of the filtration barrier. Moreover, ZFYVE28-deficiency did not affect the outcome of glomerular damage induced by injection of nephrotoxic serum. Taken together, we have identified Zfyve28 as a new molecular component of podocyte foot processes and show that it mediates EGF-signaling in podocytes. However, ZFYVE28 is not essential for the development or maintenance of the glomerulus filtration barrier.
Highlights
IntroductionThe kidney filtration barrier located in the glomerulus is composed of three layers: (1) fenestrated endothelial cells, on the inside in contact with the blood; (2) the glomerular basement membrane (GBM), which serves as foundation and support; and (3) visceral epithelial cells (named podocytes), located on the outside of the glomerular capillary
The kidney filtration barrier located in the glomerulus is composed of three layers: (1) fenestrated endothelial cells, on the inside in contact with the blood; (2) the glomerular basement membrane (GBM), which serves as foundation and support; and (3) visceral epithelial cells, located on the outside of the glomerular capillary
Zinc finger FYVE-type containing 28 (ZFYVE28) mRNA is highly enriched in podocytes in both human and mouse
Summary
The kidney filtration barrier located in the glomerulus is composed of three layers: (1) fenestrated endothelial cells, on the inside in contact with the blood; (2) the glomerular basement membrane (GBM), which serves as foundation and support; and (3) visceral epithelial cells (named podocytes), located on the outside of the glomerular capillary. All three layers forming the filtration barrier are necessary for its function, the podocyte seems to be the most critical constituent of the filter This is highlighted for instance by the fact that mutations in many podocyte-specific proteins result in proteinuria[1,2]. Mammalian cells express more than 25 different FYVE domain-containing proteins Their functions are still relatively poorly understood. Deletion of EGFR in podocytes protects mice from glomerular damage in diabetic nephropathy and rapidly progressive glomerulonephritis (RPGN). These studies demonstrate that EGFR activation has a major role in mediating podocyte damage in glomerular disease[9,10,11]
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