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HDAC5 RNA interference ameliorates acute renal injury by upregulating KLF2 and inhibiting NALP3 expression in a mouse model of oxalate nephropathy.
- Source :
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International immunopharmacology [Int Immunopharmacol] 2022 Nov; Vol. 112, pp. 109264. Date of Electronic Publication: 2022 Sep 29. - Publication Year :
- 2022
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Abstract
- Krüppel-like factor 2 (KLF2) and NLR family pyrin domain containing 3 (NALP3) are important regulators of macrophage activation in the context of various pathological conditions. NALP3 also plays an important role in the maturation of IL-1 β which is central to the pathogenesis of acute oxalate nephropathy. The functional role of KLF2 and regulation of both KLF2 and NALP3 in the pathogenesis of acute oxalate nephropathy is comparably less studied. Here, we explored the regulation of KLF2 and NALP3 by Histone deacetylase 5 (HDAC5) in oxalate crystals stimulated macrophages, and in the pathogenesis of acute oxalate nephropathy in mice. We observed upregulated expression of HDAC5 along with IL-1β, Caspase1, and NALP3, while the expression of KLF2 was downregulated in stimulated macrophages and in the renal tissue of mice with acute oxalate nephropathy. We formulated chitosan HDAC5 siRNA nanoparticles to deliver the siRNA in in-vitro and in-vivo settings. siHDAC5 treated cells exhibited decreased expression of IL-1β, and TNF-α in the supernatant, and reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1β, and IL-1β in cell lysate. Concurrently, the expression of KLF2 was upregulated in HDAC5 depleted cells upon stimulation with crystals. Mice treated with siHDAC5 nanoparticles showed protection against renal impairment with improved renal function (plasma BUN and creatinine levels), reduced inflammation (IL-1β expression), reduced accumulation of neutrophils, reduced tubular injury, reduced acute renal injury markers (KIM-1, NGAL-1), reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1β, and IL-1β. Whereas, the expression of KLF2 was significantly upregulated by depletion of HDAC5 in mice.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Creatinine
Disease Models, Animal
Histone Deacetylases genetics
Histone Deacetylases metabolism
Inflammasomes metabolism
Interleukin-1beta metabolism
Kruppel-Like Transcription Factors genetics
Kruppel-Like Transcription Factors metabolism
Lipocalin-2 metabolism
NLR Family, Pyrin Domain-Containing 3 Protein genetics
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Oxalates
RNA Interference
RNA, Small Interfering
Transcription Factors genetics
Tumor Necrosis Factor-alpha metabolism
Acute Kidney Injury chemically induced
Acute Kidney Injury genetics
Acute Kidney Injury therapy
Chitosan
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 112
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 36183679
- Full Text :
- https://doi.org/10.1016/j.intimp.2022.109264