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Title: Nephrotoxicity associated with preeclampsia in an Arginine Vasopressin induced rat pregnancy model
Authors: Ramdin, Sapna 
Keywords: Preeclampsia
Issue Date: May-2023
Introduction: Globally, preeclampsia (PE) complicates an estimated 2-8% of
pregnancies and is a leading cause of maternal and fetal morbidity and mortality. Renal
injury is closely involved in the pathophysiology of PE and is associated with future risk
of kidney disease. Identifying an early biomarker of renal dysfunction is essential for the
diagnosis and treatment of PE. Given the clinical and ethical complexities associated
with pregnancy studies in humans, animal models provide a more feasible alternative to
pregnancy research.
Aim: In view of this, this study aimed to determine the physiological and biochemical
features of the arginine vasopressin (AVP) induced pregnancy model in the Sprague
Dawley rat and to demonstrate nephrotoxicity associated with this model.
Methodology: Urine, blood and kidney samples (n = 6 per study group) were collected
from female Sprague Dawley rats, based on four study groups, viz., pregnant AVP,
pregnant saline, non-pregnant AVP, and non-pregnant saline groups. The AVP rat model
was physiologically characterized by evaluating the clinical, biochemical,
haematological and fetal parameters across all study groups. Renal injury in AVP-treated
rats was histologically determined by haematoxylin and eosin staining, as well as
immunolocalizing kidney injury molecule-1 (KIM-1) and podocalyxin in both AVPtreated and untreated kidneys using immunohistochemistry. Ultrastructural changes in
AVP-treated rats were determined by transmission electron microscopy. The Multiplex
kidney toxicity immunoassay panels were used to determine the urinary concentration of
albumin, vascular endothelial growth factor-A, clusterin, cystatin C, beta-2-
microglobulin, KIM-1, neutrophil gelatinase-associated lipocalin-2, osteopontin and
tissue inhibitor of metalloproteinases-1 in AVP-treated rats.
Key findings: Chronic infusion of AVP throughout gestation reproduced the phenotypes
viz., increased blood pressure, elevated urinary protein levels and fetal growth restriction,
characteristic of human PE development. Immunohistochemical analysis confirm KIM1 immunolocalization in the proximal convoluted tubules of AVP-treated vs. untreated groups. Comparatively, a mild immunolocalization of podocalyxin was observed in the
glomeruli of pregnant AVP-treated vs. pregnant untreated rats. Histological and
ultrastructural evaluation of the AVP-treated pregnant rats demonstrated several
abnormalities including, reduced Bowman’s space, necrosis of tubules and blood vessels,
along with podocyte effacement, glomerular basement membrane abnormalities,
podocyte nuclear crenations, mitochondrial dysfunction and cytoplasmic lysis consistent
with renal injury in PE. Our findings indicate that AVP significantly reduces the urinary
levels of vascular endothelial growth factor A and concomitantly up-regulates the urinary
expression of clusterin, cystatin C, beta-2-microglobulin, KIM-1, neutrophil gelatinaseassociated lipocalin-2, osteopontin and tissue inhibitor of metalloproteinases-1.
Conclusion: This is the first study to demonstrate that AVP induces glomerular and
tubular injury, as well as endothelial dysfunction in the pregnant Sprague Dawley rat
model. These features are characteristic of renal injury observed in PE. Furthermore,
AVP successfully elevated the urinary levels of most glomerular and tubular injury
biomarkers as well as produced histological and ultrastructural renal abnormalities
associated with human PE. Our data demonstrates the importance of kidney injury as
early detection biomarkers for PE development. The findings support the use of the AVP
rat model in future studies investigating the pathogenic processes involved in PE
Submitted in fulfillment of the requirements for the degree of Doctor of Philosophy: Health Sciences, Durban University of Technology, Durban, South Africa, 2022.
Appears in Collections:Theses and dissertations (Health Sciences)

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