Abstract
Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient‐specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole‐genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney‐specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.
Highlights
Polycystic kidney disease (PKD) is a heterogeneous group of diseases that can be inherited or acquired
We have generated induced pluripotent stem cells (iPSCs) from cystic renal epithelial cells. iPSCs from healthy renal epithelial cells have been established previously,[46,47] but this was not yet done from cyst cells
We found that our cyst-iPSCs contain somatic mutations, but only a few of these mutations were present in tubular epithelial cell (TEC) they were derived from
Summary
Polycystic kidney disease (PKD) is a heterogeneous group of diseases that can be inherited or acquired. Somatic mutations affecting the remaining healthy PKD1 allele are proposed to precede cyst initiation This hypothesis is supported by the observation that heterozygous Pkd[1] mice develop only a few cyst, whereas (kidney specific) inducible knock out of both Pkd[1] alleles results in a severe cystic phenotype including renal failure, recapitulating the human phenotype.[10] Further evidence supporting this second hit model came from mutational studies on DNA from cyst lining epithelium, isolated from human kidney tissue samples, which displayed small somatic mutations or loss of heterozygosity (LOH) in PKD1 or PKD2.11-15 the second hit might be present in genes other than the one affected in the germline. Evidence for this trans-heterozygous hypothesis is the identification of somatic mutations in PKD2 in cyst DNA from patients with a PKD1 germline
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