Abstract
The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/−) or homozygous (Pkd1RC/RC/Atm−/−) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease [1]
To investigate the mechanisms underlying the reduction in cyst growth, we investigated the effects of VE-821 and KU-60019 on cell proliferation and cytotoxicity
Current research on the role of the DNA damage response (DDR) pathway in ADPKD is very limited and, to our knowledge, this is the first study to investigate the efficacy of modulating ataxia-telangiectasia mutated (ATM) on experimental models
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease [1]. PKD1 or PKD2, which encode polycystin 1 and 2, respectively [2]. This causes sporadic formation and growth of multiple kidney cysts and a 50% lifetime risk for kidney failure by age 60 [3,4,5,6]. Emerging evidence suggests that an increased susceptibility to DNA-damaging events, genomic instability, and dysregulation in DNA damage response (DDR) signaling is feature of cystic kidney diseases [9,10,11,12,13,14,15]. We previously hypothesized that DNA damage may play a role in ADPKD pathogenesis [16], and demonstrated that the expression of the DDR signaling pathway was dysregulated in both human and early murine ADPKD [17]
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