BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury

• Published in: Biomedicine & pharmacotherapy Vol. 174; p. 116492
• Main Authors: Saiz, Maria Laura, Lozano-Chamizo, Laura, Florez, Aida Bernardo, Marciello, Marzia, Diaz-Bulnes, Paula, Corte-Iglesias, Viviana, Bernet, Cristian Ruiz, Rodrigues-Diez, Raul R., Martin-Martin, Cristina, Rodriguez-Santamaria, Mar, Fernandez-Vega, Ivan, Rodriguez, Ramon M., Diaz-Corte, Carmen, Suarez-Alvarez, Beatriz, Filice, Marco, Lopez-Larrea, Carlos
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-05-2024; Elsevier
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - prevention & control; AKI; Animals; Azepines - administration & dosage; Azepines - pharmacology; BRD4; Bromodomain Containing Proteins; Cell Cycle Proteins - antagonists & inhibitors; Disease Models, Animal; Disease Progression; ischemia reperfusion injury; JQ1; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; kidney drug delivery; Liposomes; Male; Mice; Mice, Inbred C57BL; nanobiotechnology; Nanoparticles; Nuclear Proteins; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - pathology; Reperfusion Injury - drug therapy; Reperfusion Injury - pathology; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Triazoles - administration & dosage; Triazoles - pharmacology; IRI; RdR; PAS; MRI; IBETs; ALT; DLS; kidney drug delivery; JQ1; α-SMA; BUN; OI; DMPC; CKD; HPLC; AKI; BRD4; CD; AST; AKP; H&E; MHPC; ischemia reperfusion injury; nanobiotechnology; ACN; BET; NPs; GGT; IEP; HD; TEM
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116492

Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney—an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.
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•JQ1-NPs circumvent its poor pharmacokinetics and severe side effects of this inhibitor.•JQ1-NPs reach efficiently the kidney of mice with acute kidney injury (AKI).•Administration of JQ1-NPs avoid the AKI induced by bilateral kidney IRI.•JQ1-NPs significantly reduce the recruitment of neutrophils and monocytes to the damaged kidney.•The renal fibrosis development and CKD progression is halted by JQ1-NPs treatment.