title: Renin-angiotensin system transgenic mouse model recapitulates pathophysiology similar to human preeclampsia with renal injury that may be mediated through VEGF.
abstract: Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild-type (WT) C57Bl/6 mice were cross-bred: female hAGT × male hREN for preeclampsia (PRE) model and female WT × male WT for pregnant controls (WTP). Samples were collected for plasma VEGF, sFlt1, and urine albumin. Blood pressures (BP) were monitored by telemetry. Vascular reactivity was investigated by wire myography. Kidneys and placenta were immunostained for sFlt1 and VEGF. Eleven PRE and 9 WTP mice were compared. PRE more frequently demonstrated albuminuria, glomerular endotheliosis (80% vs. 11%;P= 0.02), and placental necrosis (60% vs. 0%;P< 0.01). PRE group demonstrated declining BPs with advancing gestation. Plasma sFlt1 increased across pregnancy in PRE; VEGF did not vary. IHC demonstrated the presence of sFlt1 in glomeruli, lymphatics, and collecting tubules of PRE kidneys, suggesting excretion. VEGF immunostaining was increased specifically in the glomeruli of PRE kidneys. Placenta in PRE showed marked immunostaining for sFlt1. We conclude that this transgenic model of preeclampsia recapitulates human preeclamptic state with high fidelity, and that, vascular adaptation to pregnancy is suggested by declining BPs and reduced vascular response to PE and increased response to acetylcholine. Placental damage with resultant increased release of sFlt1, proteinuria, deficient spiral artery remodeling, and glomerular endotheliosis were observed in this model of PRE. Increased VEGF binding to glomerular endothelial cells in this model of PRE is similar to human PRE and leads us to hypothesize that renal injury in preeclampsia may be mediated through local VEGF.
authors.affiliation: Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
authors.forename: J Morgan
authors.initials: JM
authors.lastname: Denney
authors.affiliation: Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bird
authors.affiliation: Comparative Pathology Laboratory, Research Animal Resource Center, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Annette
authors.initials: A
authors.lastname: Gendron-Fitzpatrick
authors.affiliation: Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sampene
authors.affiliation: Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bird
authors.affiliation: Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin; dmshah@wisc.edu.
authors.forename: Dinesh M
authors.initials: DM
authors.lastname: Shah
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000098:blood supply*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D010920:Placenta / Q000098:blood supply*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D066253:Vascular Remodeling; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: C534931:AGT protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000808:Angiotensinogen; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D012083:Renin
keywords: VEGF; preeclampsia; renal injury; transgenic mouse model