Renal thrombotic microangiopathy in mice with combined deletion of endocytic recycling regulators EHD3 and EHD4

• Published in: PloS one Vol. 6; no. 3; p. e17838
• Main Authors: George, Manju, Rainey, Mark A, Naramura, Mayumi, Foster, Kirk W, Holzapfel, Melissa S, Willoughby, Laura L, Ying, GuoGuang, Goswami, Rasna M, Gurumurthy, Channabasavaiah B, Band, Vimla, Satchell, Simon C, Band, Hamid
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.03.2011; Public Library of Science (PLoS)
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Apoptosis; Biological activity; Biology; Biomarkers - metabolism; Cancer; Carrier Proteins - metabolism; Congenital diseases; DNA-Binding Proteins - metabolism; Endocytosis; Endothelium; Endothelium - metabolism; Feet; Gene Deletion; Genes; Genetics; Glomerular Mesangium - metabolism; Glomerular Mesangium - pathology; Glomerular Mesangium - ultrastructure; Homology; Humans; Kidney - metabolism; Kidney - pathology; Kidney - ultrastructure; Kidney diseases; Kidney transplantation; Kidneys; Laboratories; Lesions; Localization; Medicine; Mice; Nuclear Proteins - metabolism; Pathology; Physiological aspects; Podocytes - metabolism; Pre-eclampsia; Protein transport; Proteins; Proteinuria; Proteinuria - complications; Proteinuria - metabolism; Proteinuria - pathology; Receptor mechanisms; Receptors; Recycling; Regulators; Rodents; Staining and Labeling; Studies; Thickening; Thrombotic Microangiopathies - complications; Thrombotic Microangiopathies - metabolism; Thrombotic Microangiopathies - pathology; Thrombotic microangiopathy; Traffic models; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism; United States > US; Nebraska
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017838

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3-24 weeks of age. Detailed analyses of Ehd3(-/-); Ehd4(-/-) kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3(-/-); Ehd4(-/-) mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases.