1. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses
- Author
-
Kishi, Seiji, Brooks, Craig R., Taguchi, Kensei, Ichimura, Takaharu, Mori, Yutaro, Akinfolarin, Akinwande, Gupta, Navin, Galichon, Pierre, Elias, Bertha C., Suzuki, Tomohisa, Wang, Qian, Gewin, Leslie, Morizane, Ryuji, and Bonventre, Joseph V.
- Subjects
Lectins ,DNA damage ,DNA ,Chronic kidney failure -- Prevention ,DNA repair ,Ureteral obstruction ,Kidney diseases ,Fibrosis ,Ataxia telangiectasia ,Telangiectasis ,Ischemia ,Ataxia ,Health care industry ,Harvard University. Harvard Stem Cell Institute - Abstract
Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at [G.sub.2]/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.sup.+]) 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 ([ATR.sup.RPTC-/-]) 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. [ATR.sup.RPTC-/-] mice had more cells in the [G.sub.2]/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., Introduction Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and is associated with high mortality, especially in critically ill patients (1). AKI also predisposes patients to chronic [...]
- Published
- 2019
- Full Text
- View/download PDF