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

作者：Jennifer Q.J. Zhang; Sayanthooran Saravanabavan; Ashley N. Chandra; Alexandra Munt; Annette T.Y. Wong; Peter C. Harris; David C.H. Harris; Paul McKenzie; Yiping Wang; Gopala K. Rangan^*

来源：American Journal of Pathology, 2021, 106005.

DOI：10.1016/j.ajpath.2021.01.011

• polycystic kidney disease
• DNA damage
• DNA damage response

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 upregulated DDR-related genes was increased by 16.6-fold compared to normal kidney, and by 2.5-fold in cystic compared to minimally cystic tissue (P<0.0001). In end-stage human ADPKD tissue, gamma (γ)-H2AX, phosphorylated Ataxia Telangiectasia and Rad3-related (p-ATR) and AT Mutated (p-ATM) localized to cystic kidney epithelial cells. In vitro, p-ATR and p-ATM were also constitutively increased in human ADPKD tubular cells (WT 9-7, 9-12) compared to control (HK-2). Additionally, extrinsic oxidative DNA damage by H2O2 augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the 3D MDCK cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RC mice, and not altered at later timepoints 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.

• 单位
  The University of Sydney; Mayo Clinic; Royal Prince Alfred Hospital