Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic ‘second hit’ mutations. Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation of either Pkd gene can be followed by reactivation of the gene at a later time. Using this model, we show that re-expression of Pkd genes in cystic kidneys results in rapid reversal of ADPKD. Cyst cell proliferation is reduced, autophagy is activated and cystic tubules with expanded lumina lined by squamoid cells revert to normal lumina lined by cuboidal cells. Increases in inflammation, extracellular matrix deposition and myofibroblast activation are reversed, and the kidneys become smaller. We conclude that phenotypic features of ADPKD are reversible and that the kidney has an unexpected capacity for plasticity controlled at least in part by ADPKD gene function.

常染色体显性遗传性多囊肾病 (ADPKD) 中囊肿形成的启动发生在肾小管细胞因PKD1或PKD2因体细胞“二次打击”突变而变得无效时。随后的囊肿进展通过小管细胞形状、增殖和分泌的变化重塑器官。肾脏发生炎症和纤维化。我们构建了一个小鼠模型，在该模型中，任一 Pkd基因的成人失活都可以在稍后重新激活该基因。使用这个模型，我们证明了Pkd的重新表达囊性肾中的基因导致 ADPKD 的快速逆转。囊肿细胞增殖减少，自噬被激活，囊性小管内衬鳞状细胞，管腔扩大，恢复为立方细胞内衬的正常管腔。炎症增加、细胞外基质沉积和肌成纤维细胞活化被逆转，肾脏变小。我们得出结论，ADPKD 的表型特征是可逆的，并且肾脏具有意想不到的可塑性能力，至少部分由 ADPKD 基因功能控制。