title: Renal thrombotic microangiopathy in mice with combined deletion of endocytic recycling regulators EHD3 and EHD4.
abstract: 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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. manjuggm@gmail.com
authors.forename: Manju
authors.initials: M
authors.lastname: George
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rainey
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Foster
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Holzapfel
authors.forename: Laura L
authors.initials: LL
authors.lastname: Willoughby
authors.forename: GuoGuang
authors.initials: G
authors.lastname: Ying
authors.forename: Rasna M
authors.initials: RM
authors.lastname: Goswami
authors.forename: Channabasavaiah B
authors.initials: CB
authors.lastname: Gurumurthy
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004705:Endocytosis; D004727:Endothelium / Q000378:metabolism; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism; D011507:Proteinuria / Q000150:complications / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling; D057049:Thrombotic Microangiopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C543675:EHD4 protein, mouse; C470993:Ehd3 protein, mouse; D009687:Nuclear Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2