PDF(Pubmed)
Abstract：
Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.
摘要：
结节性硬化症（TSC）表现为肾囊肿和良性肿瘤，最终导致肾衰竭.TSC中促进肾囊肿形成的因素知之甚少。碳酸酐酶2（Car2）的失活显著降低，然而,Foxi1的缺失完全消除了Tsc1KO小鼠的囊肿负担。在这些研究中,我们对比了Tsc1/Car2dKO小鼠囊肿负担的个体发育与Tsc1/Foxi1dKO小鼠。与Tsc1KO相比，Tsc1/Car2dKO小鼠在47日龄时几乎没有小囊肿。然而,110天,肾脏显示出频繁且大的囊肿，其衬里中存在大量的A-插层细胞。Tsc1/Car2dKO小鼠中囊肿负荷的大小与FOxi1的表达水平相关，并与mTORC1激活成正比。这与Tsc1/FOxi1dKO小鼠形成鲜明对比，这表明在47和110日龄时都明显没有肾囊肿。RNA-seq数据表明，在110天大的Tsc1/Car2dKO小鼠中，FOxi1和肾脏集合管特异性H-ATPase亚基的显着上调。我们得出的结论是，Car2失活暂时降低了Tsc1KO小鼠的肾囊肿负担，但囊肿随着年龄的增长而增加，以及增强的FOXi1表达。
