Rapamycin-mediated suppression of renal cyst expansion in del34 Pkd1-/- mutant mouse embryos: an investigation of the feasibility of renal cyst prevention in the foetus.
Rapamycin-mediated suppression of renal cyst expansion in del34 Pkd1-/- mutant mouse embryos: an investigation of the feasibility of renal cyst prevention in the foetus.
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DOI：
10.1111/j.1440-1797.2012.01639.x
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Eccles MR
中科院分区：
文献类型：
--
作者：
Stayner C;Shields J;Slobbe L;Shillingford JM;Weimbs T;Eccles MR
多囊肾病（PKD）是一种常见的肾病综合征。隐性PKD可在最初十年内导致终末期肾病（ESRD），而由PKD 1或PKD 2基因突变引起的常染色体显性PKD（ADPKD）通常在生命的第五个十年内导致ESRD。最近发现抑制mTOR信号传导可以阻止成年ADPKD小鼠中的囊肿形成。相反，没有研究调查潜在的治疗，以防止囊肿形成在子宫内隐性PKD。考虑到纯合Pkd 1突变小鼠在子宫内表现出囊肿形成，我们决定研究子宫内mTOR抑制是否改善胎儿Pkd 1纯合突变小鼠的肾囊肿形成。方法：妊娠Pkd 1 +/−雌性小鼠（与Pkd 1 +/−雄性小鼠交配）从E14.5至E17.5接受雷帕霉素处理。解剖胎儿肾脏，基因分型，并通过囊肿大小以及发育标记物Pax 2的表达进行评价。Pkd 1 −/−肾脏中存在大量囊肿，其重量是野生型肾脏的两倍。在雷帕霉素处理的Pkd 1 −/−肾脏切片中，囊肿大小减少了三分之一，肾脏质量减少到接近野生型水平。然而，与对照胚胎相比，总包囊数没有减少。Pax 2表达和肾脏发育在雷帕霉素处理的小鼠中没有改变，但在Pkd 1 −/− null胚胎中观察到一些致死性。雷帕霉素治疗减少了Pkd 1 −/−突变小鼠的囊肿形成;因此，通过mTOR抑制来预防子宫内肾囊肿扩张是可行的。然而，选择性雷帕霉素相关的致死性限制了其作为子宫内治疗的有效性。
Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice. Methods: Pregnant Pkd1+/− female mice (mated with Pkd1+/− male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. Numerous cysts were present in Pkd1−/− kidneys, which were twice the weight of wild-type kidneys. Cyst size was reduced by a third in rapamycin-treated Pkd1−/− kidney sections and kidney mass was reduced to near wild-type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin-treated mice but some lethality was observed in Pkd1−/− null embryos. Rapamycin treatment reduces cyst formation in Pkd1−/− mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin-associated lethality limits its usefulness as a treatment in utero.
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影响因子：
64.8
作者：
DRESSLER, GR;WILKINSON, JE;WESTPHAL, H
通讯作者：
WESTPHAL, H
影响因子：
15.9
作者：
Qin, Shan;Taglienti, Mary;Kreidberg, Jordan A.
通讯作者：
Kreidberg, Jordan A.
影响因子：
3.5
作者：
Zhou, Jing;Brugarolas, James;Parada, Luis F.
通讯作者：
Parada, Luis F.
DOI：
10.1073/pnas.211191098
发表时间：
2001-10-09
影响因子：
11.1
作者：
Boulter, C;Mulroy, S;Sandford, R
通讯作者：
Sandford, R
影响因子：
16
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
通讯作者：
Sabatini, DM