包装D1
常染色体显性多囊肾病
多囊肾病
囊肿
生物
表型
细胞生物学
纤毛
内质网
伴侣(临床)
肾
病理
遗传学
医学
基因
作者
Tilman Busch,Björn Neubauer,Lars Schmitt,Isabel Cascante,Luise Knoblich,Oliver Wegehaupt,Felix Schöler,Stefan Tholen,Alexis Hofherr,Christoph Schell,Oliver Schilling,Lukas Westermann,Michael Köttgen
标识
DOI:10.1096/fj.202401763r
摘要
Abstract Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 , encoding polycystin‐1 (PC1) and polycystin‐2 (PC2), which are required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)‐resident proteins through mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an ER co‐chaperone associated with atypical ADPKD. We generated mouse models with constitutive and conditional Dnajb11 inactivation and Dnajb11 ‐deficient renal epithelial cells to investigate the mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11‐dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11‐dependent cyst formation. Proteomic analysis of Dnajb11 ‐ and Pkd1 ‐deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD.
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