Up-Regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease

摘要

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P < 0.0001). In end-stage human ADPKD tissue, gamma-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented gamma-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1(RC/RC) mice, and not altered at later time points up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.