Archives of biochemistry and biophysics · 2025
Sivelestat sodium protects against renal ischemia/reperfusion injury by reduction of NETs formation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Liu Yanqi, Xin Yu, Yuan Mengyao, Liu Yuhan, Song Yuchen, Shen Lifeng, Xiao Yu, Wang Xinran, Wang Dawei, Liu Linqiong, Liu Yuxi, Luo Yinghao, Huang Pengfei, Zhang Qianqian, Zhang Weiting, Li Hongxu, Zhou Yuxin, Wang Xibo, Yu Kaijiang, Wang Changsong
Аннотация
BACKGROUND: Ischemia-reperfusion injury (IRI) often results in renal impairment. While the presence of neutrophil extracellular traps (NETs) is consistently observed, their specific impact on IRI is not yet defined. Sivelestat sodium, an inhibitor of neutrophil elastase which is crucial for NET formation, may offer a therapeutic approach to renal IRI, warranting further research.
METHODS: A mouse model was established for early-stage renal IRI, confirmed by injury markers and histological assessments. The involvement of NETs in renal I/R was demonstrated using immunofluorescence and Western blot. Renal function and pathology were further evaluated through a comprehensive set of methods, including Periodic Acid-Schiff staining (PAS) and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), Real time Glomerular Filtration Rate (RT-GFR) monitoring, Polymerase Chain Reaction (PCR), biochemical analysis, and additional Western blot and immunofluorescence assays.
RESULTS: We firstly quantified NET expression in renal IRI mice, noting a peak at 24 h. Subsequently, sivelestat sodium treatment was administered, resulting in decreased MPO, CitH3, and attenuated tubular damage. Moreover, it resulted in a decrease in serum levels of creatinine, blood urea nitrogen (BUN), as well as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Additionally, it lowered the abundance of renal tissue inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and mitigated the levels of oxidative stress indicators malondialdehyde (MDA) and 4 Hydroxynonenal (4HNE), accompanied by a decline in renal cell apoptosis and an enhancement of GFR in renal I/R mice.
CONCLUSION: Sivelestat sodium ameliorates renal IRI by downregulating neutrophil NETs, reducing inflammation, oxidative stress, and apoptosis, thereby enhancing renal function.
METHODS: A mouse model was established for early-stage renal IRI, confirmed by injury markers and histological assessments. The involvement of NETs in renal I/R was demonstrated using immunofluorescence and Western blot. Renal function and pathology were further evaluated through a comprehensive set of methods, including Periodic Acid-Schiff staining (PAS) and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), Real time Glomerular Filtration Rate (RT-GFR) monitoring, Polymerase Chain Reaction (PCR), biochemical analysis, and additional Western blot and immunofluorescence assays.
RESULTS: We firstly quantified NET expression in renal IRI mice, noting a peak at 24 h. Subsequently, sivelestat sodium treatment was administered, resulting in decreased MPO, CitH3, and attenuated tubular damage. Moreover, it resulted in a decrease in serum levels of creatinine, blood urea nitrogen (BUN), as well as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Additionally, it lowered the abundance of renal tissue inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and mitigated the levels of oxidative stress indicators malondialdehyde (MDA) and 4 Hydroxynonenal (4HNE), accompanied by a decline in renal cell apoptosis and an enhancement of GFR in renal I/R mice.
CONCLUSION: Sivelestat sodium ameliorates renal IRI by downregulating neutrophil NETs, reducing inflammation, oxidative stress, and apoptosis, thereby enhancing renal function.