TY - JOUR AU - Kishi, Seiji AU - Brooks, Craig R. AU - Taguchi, Kensei AU - Ichimura, Takaharu AU - Mori, Yutaro AU - Akinfolarin, Akinwande AU - Gupta, Navin AU - Galichon, Pierre AU - Elias, Bertha C. AU - Suzuki, Tomohisa AU - Wang, Qian AU - Gewin, Leslie AU - Morizane, Ryuji AU - Bonventre, Joseph V. T1 - Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses PY - 2019/11/01/ AB - Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin–positive (LTL+) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr-knockout (ATRRPTC–/–) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. ATRRPTC–/– mice had more cells in the G2/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI122313 VL - 129 IS - 11 UR - https://doi.org/10.1172/JCI122313 SP - 4797 EP - 4816 PB - The American Society for Clinical Investigation ER -