BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.
Vanessa MarchantFlavia TrionfettiLucia Tejedor-SantamariaSandra Rayego-MateosDante RotiliGiulio BontempiAlessandro DomeniciPaolo MenèAntonello MaiCatalina Martín-ClearyAlberto Ortiz ArduanAdrian M RamosRaffaele StrippoliMarta Ruiz-OrtegaPublished in: Antioxidants (Basel, Switzerland) (2023)
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-κB (NF-κB) 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-α (TNF-α)-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.
Keyphrases
- oxidative stress
- diabetic rats
- nuclear factor
- induced apoptosis
- end stage renal disease
- peritoneal dialysis
- ischemia reperfusion injury
- toll like receptor
- dna damage
- inflammatory response
- mouse model
- particulate matter
- air pollution
- high glucose
- chronic kidney disease
- genome wide
- signaling pathway
- immune response
- rheumatoid arthritis
- gene expression
- heavy metals
- dna methylation
- drug induced
- cell therapy
- wastewater treatment
- stem cells
- cell proliferation
- bone marrow
- copy number
- reactive oxygen species
- transcription factor
- poor prognosis
- genome wide identification
- single cell
- lipopolysaccharide induced
- mesenchymal stem cells
- risk assessment
- drug delivery
- amino acid
- cancer therapy
- patient reported outcomes
- heat stress
- anti inflammatory
- small molecule
- prognostic factors
- optical coherence tomography
- protein protein