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Published on: November 10, 2021
Interactions between BdkrB2 and p53 genes in the developing kidney
Samir S El-Dahr1, Zubaida Saifudeen
1Tulane University School of Medicine, Department of Pediatrics, Section of Pediatric Nephrology, New Orleans, LA 70112, USA. seldahr@tulane.edu
Abstract:
Gene-environment interactions are implicated in congenital disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Work from our laboratory demonstrates the presence of genetic interactions between the bradykinin B2 receptor (BdkrB2) and the tumor suppressor protein p53 in the developing kidney. Our studies have shown that the Bdkrb2(-/-) embryos exposed to gestational salt stress develop renal dysgenesis. The underlying mechanism is p53 stabilization and mediated apoptosis and repression of the terminal epithelial differentiation program. We also uncovered a novel functional cross-talk between p53 and BdkrB2. Thus, while BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 inactivation results in the upregulation of checkpoint kinase 1 (Chk1) levels, thus potentiating phosphorylation of p53 on Ser23 by Chk1, an essential step in the pathway leading to renal dysgenesis in salt-stressed BdkrB2(-/-) mutant mice. Future studies will now focus on defining how this G-protein-coupled receptor is coupled to the activation of p53, a tumor suppressor gene that is mutated in more than 50% of all human cancers.
Insights
Gene-environment interactions cause congenital disorders. We found that bradykinin B2 receptor (BdkrB2) and p53 gene interactions in developing kidneys lead to renal dysgenesis under salt stress.
Area of Science:
- Developmental biology
- Molecular genetics
- Renal physiology
Background:
- Congenital disorders often arise from gene-environment interactions, necessitating relevant animal models.
- Genetic interactions between the bradykinin B2 receptor (BdkrB2) and the p53 tumor suppressor are crucial in kidney development.
Purpose of the Study:
- To investigate the mechanistic link between BdkrB2, p53, and renal dysgenesis under gestational salt stress.
- To elucidate the functional cross-talk between BdkrB2 and p53 in the developing kidney.
Main Methods:
- Utilized a Bdkrb2(-/-) mouse model exposed to gestational salt stress.
- Analyzed p53 stabilization, apoptosis, and gene expression patterns.
- Investigated the role of checkpoint kinase 1 (Chk1) in p53 phosphorylation.
Main Results:
- Bdkrb2(-/-) embryos under salt stress exhibited renal dysgenesis.
- This phenotype was mediated by p53 stabilization, apoptosis, and repressed epithelial differentiation.
- A novel cross-talk was identified: BdkrB2 is a p53 transcriptional target, and its inactivation upregulates Chk1, enhancing p53 phosphorylation.
Conclusions:
- Gestational salt stress combined with BdkrB2 deficiency triggers a p53-mediated pathway leading to renal dysgenesis.
- The interplay between BdkrB2, p53, and Chk1 is critical for normal kidney development and presents a potential therapeutic target.
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