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A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis
Published on: January 7, 2018
Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit
Mariana Baserga1, Merica A Hale, Xingrao Ke
1University of Utah School of Medicine, Department of Pediatrics, Division of Neonatology, PO Box 581289, Salt Lake City, UT 84158, USA. mariana.baserga@hsc.utah.edu
Insights
Uteroplacental insufficiency (UPI) impairs kidney development in infants, leading to lifelong renal issues. This study shows UPI increases kidney cell death by altering p53 protein pathways without activating a key regulator, MDM2.
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Biology
Background:
- Uteroplacental insufficiency (UPI) causes intrauterine growth restriction (IUGR), impairing fetal kidney development and increasing risks for adult hypertension.
- IUGR is linked to reduced nephron endowment and increased kidney apoptosis, with elevated p53 protein levels observed in affected rat models.
- The p53 protein's activity is regulated by phosphorylation (e.g., at Ser15) and the MDM2 protein, which promotes p53 degradation.
Purpose of the Study:
- To investigate the hypothesis that UPI increases kidney apoptosis by elevating phospho-p53 (Ser15) while suppressing the MDM2 response.
- To examine the role of UPI in regulating key kinases involved in p53 phosphorylation.
Main Methods:
- Intrauterine growth restriction (IUGR) was induced in rats via bilateral uterine artery ligation.
- Kidney tissues from IUGR and control pups were analyzed for levels of phospho-p53 (Ser15), MDM2 (mRNA and protein), and specific kinases (ATM/ATR, DNA-PK).
Main Results:
- UPI significantly increased phospho-p53 (Ser15) levels in IUGR rat kidneys.
- Levels of kinases that phosphorylate p53 (ATM/ATR, DNA-PK) were also elevated in IUGR kidneys.
- Crucially, UPI did not increase kidney MDM2 mRNA or protein levels in IUGR pups, indicating a lack of the normal inhibitory response.
Conclusions:
- UPI disrupts normal kidney development by promoting p53 phosphorylation without a compensatory increase in MDM2.
- This imbalance in the p53/MDM2 pathway may contribute to the increased apoptosis and reduced nephron endowment observed in IUGR kidneys.
- These findings highlight a potential molecular mechanism linking in utero insults to long-term kidney health issues.
Abstract:
Uteroplacental insufficiency (UPI) leads to intrauterine growth restriction (IUGR), which predisposes infants toward renal insufficiency early in life and increases the risk of kidney-related adult morbidities, such as hypertension. This compromised in utero environment has been demonstrated to impair nephrogenesis, as evidenced by a reduced nephron endowment in humans and in rats rendered IUGR by UPI. Concordantly, we have observed that IUGR rats have increased kidney p53 protein levels associated with increased apoptosis. Several factors can regulate p53 gene expression and activity, including posttranslational modifications and protein-protein interactions in the cell. Among these, two important mechanisms are 1) phosphorylation of the amino terminal serine 15 [phospho-p53 (Ser15)], which increases p53 stability and apoptotic activity, and 2) the murine double-minute (MDM2) functional circuit that limits further p53-induced apoptosis by promoting proteosomal degradation of p53. We hypothesize that UPI induces an increase in phospho-p53 (Ser15) in association with an absent MDM2 response, predisposing the kidney to increased apoptosis. To test our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. UPI significantly increased phospho-p53 (Ser15), as well as ataxia teleangiectasia-mutated kinase/A-T-related kinase and dsDNA-activated protein kinase kinase levels, which induce phosphorylation of p53. In contrast, UPI induced no increase in kidney MDM2 mRNA and protein levels in IUGR pups. We conclude that among multiple mechanisms that affect nephrogenesis, UPI induces an increase in p53 phosphorylation without a corresponding increase in MDM2 expression, and we speculate that this response may contribute to the increased apoptosis previously described in the IUGR kidney.
