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Renin-angiotensin system transgenic mouse model recapitulates pathophysiology similar to human preeclampsia with renal injury that may be mediated through VEGF.
Denney, J Morgan; Bird, Cynthia; Gendron-Fitzpatrick, Annette; Sampene, Emmanuel; Bird, Ian M; Shah, Dinesh M.
Affiliation
  • Denney JM; Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
  • Bird C; Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
  • Gendron-Fitzpatrick A; Comparative Pathology Laboratory, Research Animal Resource Center, University of Wisconsin-Madison, Madison, Wisconsin; and.
  • Sampene E; Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
  • Bird IM; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin.
  • Shah DM; Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health-Madison, Madison, Wisconsin; dmshah@wisc.edu.
Am J Physiol Renal Physiol ; 312(3): F445-F455, 2017 03 01.
Article in En | MEDLINE | ID: mdl-27927648
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Placenta / Pre-Eclampsia / Renin-Angiotensin System / Blood Pressure / Angiotensinogen / Renin / Endothelial Cells / Vascular Endothelial Growth Factor A / Kidney Diseases / Kidney Glomerulus Type of study: Prognostic_studies Limits: Animals / Female / Humans / Pregnancy Language: En Journal: Am J Physiol Renal Physiol Journal subject: FISIOLOGIA / NEFROLOGIA Year: 2017 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Placenta / Pre-Eclampsia / Renin-Angiotensin System / Blood Pressure / Angiotensinogen / Renin / Endothelial Cells / Vascular Endothelial Growth Factor A / Kidney Diseases / Kidney Glomerulus Type of study: Prognostic_studies Limits: Animals / Female / Humans / Pregnancy Language: En Journal: Am J Physiol Renal Physiol Journal subject: FISIOLOGIA / NEFROLOGIA Year: 2017 Type: Article