| First Author | Kishi S | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 11 | Pages | 4797-4816 |
| PubMed ID | 31589169 | Mgi Jnum | J:280953 |
| Mgi Id | MGI:6370339 | Doi | 10.1172/JCI122313 |
| Citation | Kishi S, et al. (2019) Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J Clin Invest 129(11):4797-4816 |
| abstractText | 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. |
