Publication: 1,25-Dihydroxyvitamin D3 mitigates high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in glomerular mesangial cells via the ROS/TXNIP/NLRP3 pathway
Authors
Bo Chen ; Chunjiang Zhang ; Lin Jia ; Xingyu Yao ; Gang Liu ; Qingyue Meng
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Publisher
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Universidad de Murcia, Departamento de Biologia Celular e Histiologia
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DOI
https://doi.org/10.14670/HH-25-021
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info:eu-repo/semantics/article
Description
Abstract
ackground. 1,25-Dihydroxyvitamin D3
(1,25(OH)2D3) is a physiologically active form of
vitamin D. Our study investigated the renoprotective
functions of 1,25(OH)2D3 in diabetic nephropathy (DN)
progression and its underlying mechanism targeting the
ROS/TXNIP/NLRP3 inflammasome pathway.
Methods. DN was induced in Wistar rats via high-fat
diet (4 weeks) and streptozotocin injection (30 mg/kg,
i.p.); hyperglycemic rats were randomized into DN and
DN + 1,25(OH)2D3 (16 μg/kg, 12 weeks) groups. Rat
mesangial HBZY-1 cells were maintained under normal
glucose (5.5 mM), high glucose (25 mM), high glucose
plus 1,25(OH)2D3 (1-50 nM), or high glucose plus N
acetylcysteine (NAC, 10 mM). Cell viability was
assessed by the CCK-8 assay. Oxidative stress
parameters (ROS via DCFH-DA fluorescence, MDA
content, SOD activity) and pyroptosis markers (LDH
release, PI/Hoechst 33342 nuclear staining) were
quantified. Renal histopathology was performed using
PAS and Masson trichrome staining. Biochemical
analyses included serum creatinine, urea nitrogen, and
24h urinary protein quantification. Molecular profiling
encompassed ELISA (IL-1β, IL-6, TNF-α, IL-18,
fibronectin, collagen IV), RT-qPCR (NOX2, NOX4,
NLRP3, ASC), western blotting (TXNIP, NLRP3, ASC,
caspase-1, IL-1β, IL-18, collagen IV, fibronectin,
laminin), and TXNIP immunofluorescence.
Results. 1,25(OH)2D3 significantly attenuated high
glucose-induced pathological alterations in HBZY-1
cells, including ROS overproduction, TXNIP
upregulation, NLRP3 inflammasome activation,
oxidative stress, inflammation, extracellular matrix
(ECM) deposition, and pyroptotic cell death.
Consistently, 1,25(OH)2D3 suppressed ROS/TXNIP/
NLRP3/caspase-1 signaling, ameliorated renal dysfunction, and mitigated histopathological damage in
DN rats.
Conclusion. 1,25(OH)2D3 confers renoprotection in
DN by inhibiting the ROS/TXNIP/NLRP3 inflamma
some axis, thereby suppressing oxidative stress,
inflammatory cytokine production, ECM accumulation,
and pyroptotic cell death in glomerular mesangial cells
and renal tissues.
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