TY - JOUR
T1 - Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses
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.
N1 - Funding Information:
We thank Hiroshi Itoh and Toshiaki Monkawa (Keio University School of Medicine, Tokyo, Japan) for the mouse anti-KSP antibody and Lorraine Racusen (Johns Hopkins Hospital, Baltimore, Maryland, USA) for the HKC-8 cells. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R37 DK39773, RO1 DK072381, and UG TR002155, to JVB); a Grant-in-Aid for Scientific Research (C, 16K09620); a Research Fellowship from the Sumitomo Life Welfare and Culture Foundation (to SK); a NIH T32 Fellowship Training Grant (DK007527, to NG); a Harvard Stem Cell Institute (HSCI) Cross-Disciplinary Fellowship Grant (to NG); a Brigham and Women’s Hospital Research Excellence Award (to NG and RM); the Novartis Foundation for Gerontological Research (to SK); the Uehara Memorial Foundation (to RM); a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad (to RM); a Brigham and Women’s Hospital Faculty Career Development Award (to RM); a Harvard Stem Cell Institute Seed Grant (to RM); Ajinomoto Co. Inc. (to RM); the DiaComp Pilot and Feasibility Program (to RM); and the NIDDK, NIH (R01 DK121101, K01DK099473, and P30 DK114809, to CRB). PG is supported by a grant from the ATIP Avenir program (INSERM-CNRS). SIM imaging was performed at the Nikon Center of Excellence at Vanderbilt University and the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126).
Funding Information:
We thank Hiroshi Itoh and Toshiaki Monkawa (Keio University School of Medicine, Tokyo, Japan) for the mouse anti-KSP antibody and Lorraine Racusen (Johns Hopkins Hospital, Baltimore, Maryland, USA) for the HKC-8 cells. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R37 DK39773, RO1 DK072381, and UG TR002155, to JVB); a Grant-in-Aid for Scientific Research (C, 16K09620); a Research Fellowship from the Sumitomo Life Welfare and Culture Foundation (to SK); a NIH T32 Fellowship Training Grant (DK007527, to NG); a Harvard Stem Cell Institute (HSCI) Cross-Disciplinary Fellowship Grant (to NG); a Brigham and Women?s Hospital Research Excellence Award (to NG and RM); the Novartis Foundation for Gerontological Research (to SK); the Uehara Memorial Foundation (to RM); a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad (to RM); a Brigham and Women?s Hospital Faculty Career Development Award (to RM); a Harvard Stem Cell Institute Seed Grant (to RM); Ajinomoto Co. Inc. (to RM); the DiaComp Pilot and Feasibility Program (to RM); and the NIDDK, NIH (R01 DK121101, K01DK099473, and P30 DK114809, to CRB). PG is supported by a grant from the ATIP Avenir program (INSERM-CNRS). SIM imaging was performed at the Nikon Center of Excellence at Vanderbilt University and the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126).
Funding Information:
Authorship note: SK and CRB contributed equally to this work. Conflict of interest: JVB and TI are co-inventors on KIM-1 patents (Molecules and methods for inhibiting shedding of KIM-1, patent no. 7696321; Kidney injury–related molecules, patent no. 6664385), which have been assigned to Partners Healthcare and licensed to several companies. JVB and RM are co-inventors on patents (PCT/ US16/52350) on organoid technologies that are assigned to Partners Healthcare. JVB is a consultant to Aldeyra, Angion, Goldilocks, and Medimmune. He is also a consultant to and holds equity in MediBeacon, Sentien Biotech, Thrasos Therapeutics, and Goldfinch Bio and has received grant support from Boehringer Ingelheim. Copyright: © 2019, American Society for Clinical Investigation. Submitted: June 6, 2018; Accepted: July 23, 2019; Published: October 7, 2019. Reference information: J Clin Invest. 2019;129(11):4797–4816. https://doi.org/10.1172/JCI122313.
Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85074377500
U2 - 10.1172/JCI122313
DO - 10.1172/JCI122313
M3 - Article
C2 - 31589169
AN - SCOPUS:85074377500
SN - 0021-9738
VL - 129
SP - 4797
EP - 4816
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -