Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease
Open Access
- 3 March 2021
- Vol. 10 (3), 532
- https://doi.org/10.3390/cells10030532
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.Keywords
Funding Information
- National Health and Medical Research Council (1164128, 1138533)
- PKD Australia (2018)
This publication has 72 references indexed in Scilit:
- How to calculate sample size in animal studies?Journal of Pharmacology and Pharmacotherapeutics, 2013
- Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severityJCI Insight, 2012
- Kinase-dead ATM protein causes genomic instability and early embryonic lethality in miceThe Journal of cell biology, 2012
- Loss of ATM kinase activity leads to embryonic lethality in miceThe Journal of cell biology, 2012
- DNA Damage ResponseCold Spring Harbor Perspectives in Biology, 2010
- Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasionMolecular Cancer Therapeutics, 2009
- Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM-Deficient LymphocytesMolecular Cell, 2009
- Small-Molecule CFTR Inhibitors Slow Cyst Growth in Polycystic Kidney DiseaseJournal of the American Society of Nephrology, 2008
- Loss of polycystin-1 causes centrosome amplification and genomic instabilityHuman Molecular Genetics, 2008
- HK-2: An immortalized proximal tubule epithelial cell line from normal adult human kidneyKidney International, 1994