PMID- 38136175
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231225
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 12
IP  - 12
DP  - 2023 Nov 29
TI  - BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by 
      Inhibition of Inflammation and Oxidative Stress.
LID - 10.3390/antiox12122055 [doi]
LID - 2055
AB  - Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney 
      diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of 
      the peritoneal membrane (PM) through mechanisms involving the activation of the 
      inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to 
      filtration failure. Peritoneal damage depends on a complex interaction among 
      external stimuli, intrinsic properties of the PM, and subsequent activities of 
      the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain 
      and extra-terminal domain (BET) proteins have shown beneficial effects on 
      different experimental preclinical diseases, mainly by inhibiting proliferative 
      and inflammatory responses. However the effect of BET inhibition on peritoneal 
      damage has not been studied. To this aim, we have evaluated the effects of 
      treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage 
      induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the 
      CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 
      decreased gene overexpression of proinflammatory and profibrotic markers, 
      together with an inhibition of the nuclear factor-kappaB (NF-kappaB) pathway. 
      Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related 
      factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH 
      oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To 
      corroborate the in vivo findings, we evaluated the effects of the BET inhibitor 
      JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A 
      cell line. JQ1 inhibited tumor necrosis factor-alpha (TNF-alpha)-induced proinflammatory 
      gene upregulation and restored MMT phenotype changes, together with the 
      downmodulation of oxidative stress. Taken together, these results suggest that 
      BET inhibitors may be a potential therapeutic option to ameliorate peritoneal 
      damage.
FAU - Marchant, Vanessa
AU  - Marchant V
AUID- ORCID: 0000-0002-2767-0229
AD  - Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, 
      IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, 
      28040 Madrid, Spain.
AD  - RICORS2040, 28029 Madrid, Spain.
FAU - Trionfetti, Flavia
AU  - Trionfetti F
AUID- ORCID: 0000-0002-7327-194X
AD  - Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro 
      Spallanzani IRCCS, 00149 Rome, Italy.
AD  - Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
FAU - Tejedor-Santamaria, Lucia
AU  - Tejedor-Santamaria L
AUID- ORCID: 0000-0003-4295-7284
AD  - Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, 
      IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, 
      28040 Madrid, Spain.
AD  - RICORS2040, 28029 Madrid, Spain.
FAU - Rayego-Mateos, Sandra
AU  - Rayego-Mateos S
AUID- ORCID: 0000-0001-6874-2359
AD  - Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, 
      IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, 
      28040 Madrid, Spain.
AD  - RICORS2040, 28029 Madrid, Spain.
FAU - Rotili, Dante
AU  - Rotili D
AUID- ORCID: 0000-0002-8428-8763
AD  - Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 
      Rome, Italy.
FAU - Bontempi, Giulio
AU  - Bontempi G
AD  - Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro 
      Spallanzani IRCCS, 00149 Rome, Italy.
AD  - Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
FAU - Domenici, Alessandro
AU  - Domenici A
AD  - Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University 
      Hospital, Sapienza University of Rome, 00189 Rome, Italy.
FAU - Mene, Paolo
AU  - Mene P
AUID- ORCID: 0000-0001-6395-6227
AD  - Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University 
      Hospital, Sapienza University of Rome, 00189 Rome, Italy.
FAU - Mai, Antonello
AU  - Mai A
AUID- ORCID: 0000-0001-9176-2382
AD  - Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 
      Rome, Italy.
FAU - Martin-Cleary, Catalina
AU  - Martin-Cleary C
AD  - Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, 
      Universidad Autonoma de Madrid, 28040 Madrid, Spain.
FAU - Ortiz, Alberto
AU  - Ortiz A
AUID- ORCID: 0000-0002-9805-9523
AD  - RICORS2040, 28029 Madrid, Spain.
AD  - Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, 
      Universidad Autonoma de Madrid, 28040 Madrid, Spain.
FAU - Ramos, Adrian M
AU  - Ramos AM
AD  - RICORS2040, 28029 Madrid, Spain.
AD  - Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, 
      Universidad Autonoma de Madrid, 28040 Madrid, Spain.
FAU - Strippoli, Raffaele
AU  - Strippoli R
AUID- ORCID: 0000-0003-3483-8381
AD  - Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro 
      Spallanzani IRCCS, 00149 Rome, Italy.
AD  - Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
FAU - Ruiz-Ortega, Marta
AU  - Ruiz-Ortega M
AUID- ORCID: 0000-0002-1495-6535
AD  - Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, 
      IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, 
      28040 Madrid, Spain.
AD  - RICORS2040, 28029 Madrid, Spain.
LA  - eng
PT  - Journal Article
DEP - 20231129
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC10740563
OTO - NOTNLM
OT  - BET proteins
OT  - JQ1
OT  - NRF2
OT  - inflammation
OT  - oxidation
OT  - peritoneal damage
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analysis, or interpretation of the data; 
      in the writing of the manuscript, or in the decision to publish the results.
EDAT- 2023/12/23 12:44
MHDA- 2023/12/23 12:45
PMCR- 2023/11/29
CRDT- 2023/12/23 01:02
PHST- 2023/10/21 00:00 [received]
PHST- 2023/11/22 00:00 [revised]
PHST- 2023/11/23 00:00 [accepted]
PHST- 2023/12/23 12:45 [medline]
PHST- 2023/12/23 12:44 [pubmed]
PHST- 2023/12/23 01:02 [entrez]
PHST- 2023/11/29 00:00 [pmc-release]
AID - antiox12122055 [pii]
AID - antioxidants-12-02055 [pii]
AID - 10.3390/antiox12122055 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2023 Nov 29;12(12):2055. doi: 10.3390/antiox12122055.