[HTML][HTML] Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses
The Journal of clinical investigation, 2019•Am Soc Clin Investig
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 …
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 …
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.
The Journal of Clinical Investigation