PMID- 36857499
OWN - NLM
STAT- MEDLINE
DCOM- 20230303
LR  - 20240302
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 34
IP  - 3
DP  - 2023 Mar 1
TI  - Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling 
      Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 during AKI 
      Recovery.
PG  - 394-411
LID - 10.1681/ASN.0000000000000024 [doi]
AB  - SIGNIFICANCE STATEMENT: Cells undergoing necrosis release extracellular high 
      mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in 
      mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 
      antagonism with small molecules, affects initial ischemic tubular necrosis and 
      immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the 
      contrary, tubular cell-specific HMGB1 deficiency, and even late-onset 
      pharmacological HMGB1 inhibition, increased functional and structural recovery 
      from AKI, indicating that intracellular HMGB1 partially counters the effects of 
      extracellular HMGB1. In vitro studies indicate that intracellular HMGB1 decreases 
      resilience of tubular cells from prolonged ischemic stress, as in unilateral IRI. 
      Intracellular HMGB1 is a potential target to enhance kidney regeneration and to 
      improve long-term prognosis in AKI. BACKGROUND: Late diagnosis is a hurdle for 
      treatment of AKI, but targeting AKI-CKD transition may improve outcomes. High 
      mobility group box-1 (HMGB1) is a nuclear regulator of transcription and a driver 
      of necroinflammation in AKI. We hypothesized that HMGB1 would also modulate 
      AKI-CKD transition in other ways. METHODS: We conducted single-cell transcriptome 
      analysis of human and mouse AKI and mouse in vivo and in vitro studies with 
      tubular cell-specific depletion of Hmgb1 and HMGB1 antagonists. RESULTS: HMGB1 
      was ubiquitously expressed in kidney cells. Preemptive HMGB1 antagonism with 
      glycyrrhizic acid (Gly) and ethyl pyruvate (EP) did not affect postischemic AKI 
      but attenuated AKI-CKD transition in a model of persistent kidney hypoxia. 
      Consistently, tubular Hmgb1 depletion in Pax8 rtTA, TetO Cre, Hmgb1fl/fl mice did 
      not protect from AKI, but from AKI-CKD transition. In vitro studies confirmed 
      that absence of HMGB1 or HMGB1 inhibition with Gly and EP does not affect 
      ischemic necrosis of growth-arrested differentiated tubular cells but increased 
      the resilience of cycling tubular cells that survived the acute injury to 
      oxidative stress. This effect persisted when neutralizing extracellular HMGB1 
      with 2G7. Consistently, late-onset HMGB1 blockade with EP started after the peak 
      of ischemic AKI in mice prevented AKI-CKD transition, even when 2G7 blocked 
      extracellular HMGB1. CONCLUSION: Treatment of AKI could become feasible when ( 1 
      ) focusing on long-term outcomes of AKI; ( 2 ) targeting AKI-CKD transition with 
      drugs initiated after the AKI peak; and ( 3 ) targeting with drugs that block 
      HMGB1 in intracellular and extracellular compartments.
CI  - Copyright (c) 2023 by the American Society of Nephrology.
FAU - Zhao, Zhi Bo
AU  - Zhao ZB
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Marschner, Julian A
AU  - Marschner JA
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Iwakura, Takamasa
AU  - Iwakura T
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Li, Chenyu
AU  - Li C
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Motrapu, Manga
AU  - Motrapu M
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Kuang, Meisi
AU  - Kuang M
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
FAU - Popper, Bastian
AU  - Popper B
AD  - Biomedical Center, Core Facility Animal Models, LMU Munchen, Munich, Germany.
FAU - Linkermann, Andreas
AU  - Linkermann A
AD  - Division of Nephrology, Department of Internal Medicine 3, University Hospital 
      Carl Gustav Carus at the Technische Universitat Dresden, Dresden, Germany.
FAU - Klocke, Jan
AU  - Klocke J
AD  - Department of Nephrology and Intensive Care, Charite-Universitatsmedizin Berlin, 
      Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, 
      Berlin, Germany.
FAU - Enghard, Philipp
AU  - Enghard P
AD  - Department of Nephrology and Intensive Care, Charite-Universitatsmedizin Berlin, 
      Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, 
      Berlin, Germany.
FAU - Muto, Yoshiharu
AU  - Muto Y
AD  - Division of Nephrology, Department of Medicine, Washington University in St. 
      Louis, St. Louis, Missouri.
FAU - Humphreys, Benjamin D
AU  - Humphreys BD
AD  - Division of Nephrology, Department of Medicine, Washington University in St. 
      Louis, St. Louis, Missouri.
AD  - Department of Developmental Biology, Washington University in St. Louis, St. 
      Louis, Missouri.
FAU - Harris, Helena Erlandsson
AU  - Harris HE
AD  - Departments of Rheumatology and of Medicine Solna, Center for Molecular Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
FAU - Romagnani, Paola
AU  - Romagnani P
AD  - Department of Experimental and Biomedical Sciences "Mario Serio" and Nephrology 
      and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
FAU - Anders, Hans-Joachim
AU  - Anders HJ
AD  - Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der 
      Universitat Munchen, LMU Munchen, Munich, Germany.
LA  - eng
GR  - UC2 DK126024/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230117
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (HMGB1 Protein)
RN  - 6FO62043WK (Glycyrrhizic Acid)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *HMGB1 Protein
MH  - Kidney
MH  - Regeneration
MH  - Epithelial Cells
MH  - Oxidative Stress
MH  - Glycyrrhizic Acid
MH  - *Acute Kidney Injury
MH  - *Renal Insufficiency, Chronic
PMC - PMC10103235
COIS- J.A. Marschner reports Speakers Bureau: MediBeacon Inc. A. Linkermann reports 
      Consultancy: Alexion, Genentech, and HBM; Research Funding: Apogenix, Else 
      Kroner-Fresenius Foundation, Fresenius, Novartis, Pfizer, and Wilhelm Sander 
      Foundation; Honoraria: Alexion, Genentech, and Novartis; and Patents or 
      Royalties: patent for Nec-1f, a combined inhibitor of necroptosis and ferroptosis 
      (no. 20160943.5). P. Enghard reports Consultancy: Advisory Board Glaxo Smith 
      Klein GSK; Ownership Interest: Gilead Stocks; Honoraria: Akademie der Nieren, 
      AstraZeneca, BDI, GlaxoSmithKline, and NAWBerlin; and Patents or Royalties: 
      submitted several patents on urinary cells as biomarkers and of a solution for 
      conserving urinary cells for subsequent analysis using flow cytometry. B.D. 
      Humphreys reports Consultancy: Chinook Therapeutics, Janssen, and Pfizer; 
      Ownership Interest: Chinook Therapeutics; Research Funding: Chinook Therapeutics, 
      Janssen, and Pfizer; Honoraria: 10X Genomics; Patents or Royalties: Evotec, AG; 
      and Advisory or Leadership Role: Seminars in Nephrology Editorial Board, Kidney 
      International Editorial Board, JCI Insight Editorial Board, American Journal of 
      Physiology Renal Physiology Editorial Board, RegMed XB, Regenerative Medicine 
      Crossing Borders SAB, ASCI President-elect, Chinook Therapeutics SAB, and Board 
      of Scientific Advisors NIDDK. P. Romagnani reports Research Funding: AstraZeneca. 
      H. Anders reports Consultancy: AstraZeneca, Bayer, GSK, Janssen, Kezar, Novartis, 
      Previpharma, Sanofi, and Vifor; Research Funding: Boehringer-Ingelheim; 
      Honoraria: Lilly, and Otsuka; and Advisory or Leadership Role: JASN, and NDT. 
      Because H.-J. Anders is an associate editor of the Journal of the American 
      Society of Nephrology, he was not involved in the peer review process for this 
      manuscript. A guest editor oversaw the peer review and decision-making process 
      for this manuscript.
EDAT- 2023/03/02 06:00
MHDA- 2023/03/04 06:00
PMCR- 2024/03/01
CRDT- 2023/03/01 14:52
PHST- 2021/12/28 00:00 [received]
PHST- 2022/10/22 00:00 [accepted]
PHST- 2023/03/02 06:00 [pubmed]
PHST- 2023/03/04 06:00 [medline]
PHST- 2023/03/01 14:52 [entrez]
PHST- 2024/03/01 00:00 [pmc-release]
AID - 00001751-202303000-00009 [pii]
AID - JASN-2022-001036 [pii]
AID - 10.1681/ASN.0000000000000024 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2023 Mar 1;34(3):394-411. doi: 10.1681/ASN.0000000000000024. 
      Epub 2023 Jan 17.