Renin-angiotensin system transgenic mouse model recapitulates pathophysiology similar to human preeclampsia with renal injury that may be mediated through VEGF

Autor: J. Morgan Denney, Cynthia E. Bird, Annette Gendron-Fitzpatrick, Dinesh Shah, Ian M. Bird, Emmanuel Sampene
Rok vydání: 2017
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
Genetically modified mouse
medicine.medical_specialty
Physiology
Placenta
Transgene
VEGF receptors
Kidney Glomerulus
Angiotensinogen
Blood Pressure
Gestational Age
Mice
Transgenic
Vascular Remodeling
030204 cardiovascular system & hematology
Biology
Preeclampsia
Renin-Angiotensin System
03 medical and health sciences
0302 clinical medicine
Pre-Eclampsia
Renal injury
Pregnancy
Internal medicine
Renin
Renin–angiotensin system
medicine
Albuminuria
Animals
Humans
Genetic Predisposition to Disease
Vascular Endothelial Growth Factor Receptor-1
Endothelial Cells
medicine.disease
Pathophysiology
Mice
Inbred C57BL
Vasodilation
Disease Models
Animal
Phenotype
030104 developmental biology
Endocrinology
Vasoconstriction
biology.protein
Female
Kidney Diseases
Signal Transduction
Zdroj: American Journal of Physiology-Renal Physiology. 312:F445-F455
ISSN: 1522-1466
1931-857X
Popis: 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.
Databáze: OpenAIRE
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