Suppression of ureteric bud apoptosis rescues nephron endowment and adult renal function in Pax2 mutant mice
Suppression of ureteric bud apoptosis rescues nephron endowment and adult renal function in Pax2 mutant mice
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DOI：
10.1681/asn.2005101074
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发表时间：
2006-06-01
影响因子：
13.6
通讯作者：
Goodyer, Paul
中科院分区：
文献类型：
--
作者：
Dziarmaga, Alison;Eccles, Michael;Goodyer, Paul
确定先天性肾单位数目的分子机制尚不清楚。然而，具有适度次优肾单位数目的人可能处于原发性高血压的增加的风险中，并且那些在出生时具有更严重肾单位缺陷的人可能发展为进行性肾功能不全。已经提出了一个胚胎肾发育过程中的分支形态发生模型，其中输尿管芽分支的程度取决于对程序性细胞死亡的抑制。这项研究表明，杂合Pax2突变小鼠的细胞凋亡增加和输尿管芽分支减少与出生时肾单位数量减少40%相关。这导致出生后肾小球肥大和长期肾功能不全的情况下肾小球硬化。为了确定单独恢复抗凋亡因子是否足以挽救这些小鼠中的肾单位缺陷，将在PAX2启动子控制下的BCL 2转基因靶向输尿管芽。该转基因抑制输尿管芽谱系中的程序性细胞死亡，在出生时将肾单位数量增加至野生型同窝仔的90%，并在1岁时使肾功能正常化。这些观察结果有力地支持了这一假设，即控制输尿管芽细胞凋亡的因素是先天性肾单位禀赋的强有力的决定因素。
The molecular mechanisms that set congenital nephron number are unknown. However, humans with modest suboptimal nephron number may be at increased risk for essential hypertension, and those with more severe nephron deficits at birth may develop progressive renal insufficiency. A model of branching morphogenesis during fetal kidney development in which the extent of ureteric bud arborization is dependent on suppression of programmed cell death has been proposed. This study shows that the increased apoptosis and reduced ureteric bud branching of heterozygous Pax2 mutant mice is associated with 40% decrease in nephron number at birth. This leads to postnatal glomerular hypertrophy and long-term renal insufficiency in the absence of glomerulosclerosis. To determine whether restoration of antiapoptotic factors alone is sufficient to rescue the nephron deficit in these mice, a BCL2 transgene that is under the control of the PAX2 promoter was targeted to the ureteric bud. The transgene suppressed programmed cell death in the ureteric bud lineage, increased nephron number to 90% of that of wild-type littermates at birth, and normalized renal function at 1 yr. These observations lend strong support to the hypothesis that factors that control ureteric bud apoptosis are powerful determinants of congenital nephron endowment.