A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1
A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1
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DOI：
10.1038/nm1675
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发表时间：
2007-12-01
期刊：
影响因子：
82.9
通讯作者：
Germino, Gregory G.
中科院分区：
文献类型：
--
作者：
Piontek, Klaus;Menezes, Luis F.;Germino, Gregory G.
常染色体显性遗传性多囊肾病是终末期肾病的重要原因，目前尚无有效的治疗方法[1]。PKD1(编码多囊蛋白-1的基因)的突变是这种疾病的主要原因。这种疾病开始于子宫，进展缓慢，但尚不清楚囊性病变是否是成人生活中的一个持续过程。我们现在发现，在小鼠出生后第13天之前，PKD1的失活会在3周内导致严重的囊性肾脏，而在第14天和以后的失活只会在5个月后导致囊性肾。我们发现，囊性样本的细胞增殖并不明显高于年龄匹配的对照组，但对PKD1失活的反应突然发生变化，对应于肾脏生长过程中先前未知的刹车点和基因表达的显著变化。这些发现表明，PKD1失活的影响是由一个发育开关定义的，该开关标志着肾脏终末成熟过程的结束。我们的研究表明，PKD1调节发育中和成年肾脏的小管形态，但失活的病理后果由器官的发育状态决定。这些结果对临床了解该病和治疗方法具有重要意义。
Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy(1). Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero(2) and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.