Abstract: SA-PO077
Inhibition of Ataxia-Telangiectasia Mutated Exacerbates AKI by Activating p53 Signaling in Mice
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Uehara, Masahiro, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Yamashita, Noriyuki, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan
Background
The DNA damage response (DDR) after kidney injury induces cell cycle arrest in renal tubular epithelial cells. Cell cycle-arrested tubular epithelia secrete pro-fibrotic cytokines, thereby promoting interstitial fibrosis in a paracrine manner. Phosphorylation of ataxia-telangiectasia mutated (ATM) is the initial step in DDR and subsequent cell cycle arrest. ATM inhibitors are emerging cancer drug candidates; however, the effects of ATM inhibition on the injured kidney have not been explored.
Methods
We administered KU55933, a selective ATM inhibitor, to cisplatin-treated mice and UUO mouse model. In order to specifically investigate the underlying mechanism in tubular epithelia, we isolated the proximal tubular epithelia by FACS from bigenic SLC34a1-CreERt2; R26tdTomato proximal tubular-specific reporter mice.
Results
ATM inhibition did not ameliorate but rather exacerbated cisplatin-induced DNA damage and tubular injury, thereby increasing mortality. Numerous tubules with denuded tubular basement membrane where the tubular epithelia had completely detached were observed in the kidneys of mice that received KU55933 and cisplatin. Analysis of isolated tubular epithelia revealed that KU55933 upregulated p53 and subsequent pro-apoptotic signaling, such as PUMA and Bax expression, in tubular epithelia of cisplatin-treated mice, leading to marked mitochondrial injury and apoptosis. In addition, ATM inhibition did not increase the nuclear expression of MutL homologue 1 in tubular epithelia of cisplatin-treated mice, suggesting that DNA mismatch repair after tubular injury was not sufficient to prevent cisplatin-induced tubular injury. Lastly, we investigated the effect of ATM inhibition on UUO kidney and found that KU55933 did not ameliorate the kidney fibrosis.
Conclusion
Our study suggested that ATM inhibition does not increase DNA repair after cisplatin-induced DNA damage and exacerbates tubular injury through the upregulation of p53-dependent pro-apoptotic signaling. Acute kidney injury must be carefully monitored when ATM inhibitors become available in clinical practice in the future.