Piontek Klaus, Menezes Luis F, Garcia-Gonzalez Miguel A, Huso David L, Germino Gregory G
Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
Nat Med. 2007 Dec;13(12):1490-5. doi: 10.1038/nm1675. Epub 2007 Oct 28.
Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero 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.
常染色体显性多囊肾病是终末期肾病的一个重要病因，目前尚无经证实的治疗方法。PKD1（编码多囊蛋白-1的基因）突变是该疾病的主要病因。该病始于子宫内且进展缓慢，但尚不清楚囊肿形成在成年期是否为一个持续的过程。我们现在发现，在出生后第13天之前使小鼠体内的Pkd1失活，会在3周内导致严重的多囊肾，而在第14天及之后使Pkd1失活则仅在5个月后才会出现囊肿。我们发现，囊性标本中的细胞增殖并不比年龄匹配的对照明显更高，但对Pkd1失活的突然反应变化对应于肾脏生长过程中一个此前未被认识到的转折点以及基因表达的显著变化。这些发现表明，Pkd1失活的影响由一个发育开关所决定，该开关标志着终末期肾脏成熟过程的结束。我们的研究表明，Pkd1在发育中的肾脏和成年肾脏中均调节肾小管形态，但失活的病理后果由器官的发育状态所决定。这些结果对该疾病的临床理解和治疗方法具有重要意义。
