Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 11, Pages 4797-4816Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122313
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH [R37 DK39773, RO1 DK072381, UG TR002155]
- NIH [CA68485, DK20593, DK58404, DK59637, EY08126]
- Sumitomo Life Welfare and Culture Foundation
- NIH T32 Fellowship Training Grant [DK007527]
- Harvard Stem Cell Institute (HSCI) Cross-Disciplinary Fellowship Grant
- Brigham and Women's Hospital Research Excellence Award
- Novartis Foundation for Gerontological Research
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad
- Brigham and Women's Hospital Faculty Career Development Award
- Harvard Stem Cell Institute Seed Grant
- Ajinomoto Co. Inc.
- DiaComp Pilot and Feasibility Program
- NIDDK, NIH [R01 DK121101, K01DK099473, P30 DK114809]
- ATIP Avenir program (INSERM-CNRS)
- [16K09620]
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Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G(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 tetrogonolobus 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 (ATR(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(RPTC-/-) mice had more cells in the G(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.
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