Bradykinin synthesis and B2 receptor expression are transiently up-regulated in the distal nephron during development. Preliminary studies show that gestational high salt induces collecting system dysgenesis in pups with targeted deletion of the B2 receptor. The collecting ducts of salt stressed B2-receptor null pups exhibit up-regulated expression of the EGF-Receptor and an increased number of apoptotic cells. Distal nephron differentiation progresses normally in non-salt stressed B2 receptor null pups. The objective of this proposal is to examine the role of the bradykinin-B2 receptor in distal nephron development during gestational salt stress.
In Specific Aim 1, the role of maternal factors in promoting the abnormal renal phenotype exhibited by salt-stressed B2 null pups will be examined. The hypothesis that gestational salt-stress perturbs collecting system development in B2 null embryos will be tested using molecular markers that define discrete stages of renal epithelial differentiation. Experiments proposed in Specific Aims 2 will test the hypothesis that gestational salt stress activates p53 mediated apoptois in the absence of functional B2 receptors. The expression pattern of p53 and its downstream targets, Bcl-2 and Bax, will be analyzed in conjunction with in situ detection of nuclear DNA fragmentation. Double homozygous B2/p53 null mice will be generated to test the hypothesis that p53 activation plays a role in B2 null abnormal renal phenotype.
Specific Aim 3 focuses on the role of EGF-receptor signalling in the generation of B2 null renal abnormalities. EGF-receptor mRNA, protein levels and functional activity will be analyzed. The effects of partial loss and gain of EGF-receptor function will be examined.
The final aim will determine if disordered distal nephrogenesis is linked to the development of hypertension and impaired renal function in B2 receptor null mice. These studies will examine the effect of B2 receptor ablation on the maturation of blood pressure, if developmentally stressed B2 receptor null mice exhibit impaired renal function, the effects of B2 receptor inactivation on the ontogeny of the renin-angiotensin system, and the role of ATII in mediating salt-sensitive hypertension in B2 null mice.
| Kopkan, Libor; Husková, Zuzana; Jíchová, Šárka et al. (2016) Conditional knockout of collecting duct bradykinin B2 receptors exacerbates angiotensin II-induced hypertension during high salt intake. Clin Exp Hypertens 38:1-9 |
| Hilliard, Sylvia A; Yao, Xiao; El-Dahr, Samir S (2014) Mdm2 is required for maintenance of the nephrogenic niche. Dev Biol 387:1-14 |
| Yan, Lei; Yao, Xiao; Bachvarov, Dimcho et al. (2014) Genome-wide analysis of gestational gene-environment interactions in the developing kidney. Physiol Genomics 46:655-70 |
| McLaughlin, Nathan; Wang, Fenglin; Saifudeen, Zubaida et al. (2014) In situ histone landscape of nephrogenesis. Epigenetics 9:222-35 |
| El-Dahr, Samir; Hilliard, Sylvia; Aboudehen, Karam et al. (2014) The MDM2-p53 pathway: multiple roles in kidney development. Pediatr Nephrol 29:621-7 |
| El-Dahr, Samir S; Saifudeen, Zubaida (2013) Interactions between BdkrB2 and p53 genes in the developing kidney. Biol Chem 394:347-51 |
| Rosenberg, Stacy L; Chen, Shaowei; McLaughlin, Nathan et al. (2011) Regulation of kidney development by histone deacetylases. Pediatr Nephrol 26:1445-52 |
| Chen, Shaowei; Bellew, Christine; Yao, Xiao et al. (2011) Histone deacetylase (HDAC) activity is critical for embryonic kidney gene expression, growth, and differentiation. J Biol Chem 286:32775-89 |
| Hilliard, Sylvia; Aboudehen, Karam; Yao, Xiao et al. (2011) Tight regulation of p53 activity by Mdm2 is required for ureteric bud growth and branching. Dev Biol 353:354-66 |
| Song, Renfang; Spera, Melissa; Garrett, Colleen et al. (2010) Angiotensin II AT2 receptor regulates ureteric bud morphogenesis. Am J Physiol Renal Physiol 298:F807-17 |
Showing the most recent 10 out of 37 publications
