Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis
Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis
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DOI：
10.1152/ajprenal.90378.2008
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发表时间：
2008-11-01
影响因子：
4.2
通讯作者：
Dipp, Susana
中科院分区：
文献类型：
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作者：
El-Dahr, Samir S.;Aboudehen, Karam;Dipp, Susana
El-Dahr SS，Aboudehen K，Dipp S.缓激肽B-2受体缺失小鼠在p53基因中Ser（23）-至-Ala置换可保护其免于肾发育不全。美国肾脏生理学杂志295：F1404-F1413，2008年。首次发表于2008年8月27日; doi：10.1152/ajprenal.90378.2008。在肾器官发生过程中，肿瘤抑制蛋白p53和缓激肽B2受体（BdkrB2）之间存在生理性串扰。因此，尽管BdkrB2是p53介导的转录激活的靶点，但BdkrB2是限制p53促凋亡活性所必需的。我们以前证明，BdkrB2（-/-）胚胎暴露于妊娠期盐应激发展肾发育不全的p53介导的肾祖细胞凋亡和终末分化程序的抑制的结果。与野生型肾脏相比，BdkrB2（-/-）表达异常高水平的检查点激酶（Chk1），其通过Ser（23）磷酸化激活p53。为了确定p53（S23）磷酸化的功能相关性，我们通过将BdkrB2（-/-）与p53（S23A）敲入小鼠杂交，产生了一种在p53基因中携带纯合Ser（23）-to-Ala（S23A）突变的BdkrB2（-/-）小鼠复合品系。与盐应激的BdkrB2（-/-）幼仔不同，其表现出肾发育不全，纯合子S23A; BdkrB2（-/-）同窝仔受到保护并具有正常的肾发育。杂合子S23A; BdkrB2（-/-）小鼠具有中间表型。p53-S23A取代与细胞凋亡的改善和肾发生和肾小管发生的恢复标志物相关。终末分化基因的实时定量RT-PCR显示，S23A取代恢复了水通道蛋白2、Na-Cl协同转运蛋白、Na-K-2Cl协同转运蛋白、Na-碳酸氢盐协同转运蛋白和Sglt1的正常表达模式。我们的结论是，p53丝氨酸（23）磷酸化是介导的易感性BdkrB2（-/-）突变体肾发育不全的信号通路中的一个重要步骤。
El-Dahr SS, Aboudehen K, Dipp S. Bradykinin B-2 receptor null mice harboring a Ser(23)-to-Ala substitution in the p53 gene are protected from renal dysgenesis. Am J Physiol Renal Physiol 295: F1404-F1413, 2008. First published August 27, 2008; doi:10.1152/ajprenal.90378.2008.-A physiological cross talk operates between the tumor suppressor protein p53 and the bradykinin B2 receptor (BdkrB2) during renal organogenesis. Thus, although BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 is required to restrict p53 proapoptotic activity. We previously demonstrated that BdkrB2(-/-) embryos exposed to gestational salt stress develop renal dysgenesis as a result of p53-mediated apoptosis of nephron progenitors and repression of the terminal differentiation program. Compared with wild-type kidneys, BdkrB2(-/-) express abnormally high levels of the Checkpoint kinase (Chk1), which activates p53 via Ser(23) phosphorylation. To define the functional relevance of p53(S23) phosphorylation, we generated a compound strain of BdkrB2(-/-) mice harboring a homozygous Ser(23)-to-Ala (S23A) mutation in the p53 gene by crossing BdkrB2(-/-) with p53(S23A) knockin mice. Unlike salt-stressed BdkrB2(-/-) pups, which exhibit renal dysgenesis, homozygous S23A; BdkrB2(-/-) littermates are protected and have normal renal development. Heterozygous S23A; BdkrB2(-/-) mice have an intermediate phenotype. The p53-S23A substitution was associated with amelioration of apoptosis and restored markers of nephrogenesis and tubulogenesis. Real-time quantitative RT-PCR of terminal differentiation genes demonstrated that the S23A substitution restored normal expression patterns of aquaporin-2, Na-Cl cotransporter, Na-K-2Cl cotransporter, Na-bicarbonate cotransporter, and Sglt1. We conclude that p53 phosphorylation on Ser(23) is an essential step in the signaling pathway mediating the susceptibility of BdkrB2(-/-) mutants to renal dysgenesis.