Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury
Background: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2017-01-01
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| Series: | Chinese Medical Journal |
| Subjects: | |
| Online Access: | http://www.cmj.org/article.asp?issn=0366-6999;year=2017;volume=130;issue=18;spage=2163;epage=2169;aulast=Huang |
| _version_ | 1819238230588915712 |
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| author | Rong-Shuang Huang Jiao-Jiao Zhou Yu-Ying Feng Min Shi Fan Guo Shen-Ju Gou Stephen Salerno Liang Ma Ping Fu |
| author_facet | Rong-Shuang Huang Jiao-Jiao Zhou Yu-Ying Feng Min Shi Fan Guo Shen-Ju Gou Stephen Salerno Liang Ma Ping Fu |
| author_sort | Rong-Shuang Huang |
| collection | DOAJ |
| description | Background: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway.
Methods: C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected.
Results: In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-α, IL-6, and IL-1β) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-κB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01).
Conclusion: The pharmacological inhibition of TLR4/NF-κB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration. |
| first_indexed | 2024-12-23T13:32:55Z |
| format | Article |
| id | doaj.art-7a56a93b46e843089e0e45f2bc92a6a2 |
| institution | Directory Open Access Journal |
| issn | 0366-6999 |
| language | English |
| last_indexed | 2024-12-23T13:32:55Z |
| publishDate | 2017-01-01 |
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| record_format | Article |
| series | Chinese Medical Journal |
| spelling | doaj.art-7a56a93b46e843089e0e45f2bc92a6a22022-12-21T17:45:07ZengWolters KluwerChinese Medical Journal0366-69992017-01-01130182163216910.4103/0366-6999.213406Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney InjuryRong-Shuang HuangJiao-Jiao ZhouYu-Ying FengMin ShiFan GuoShen-Ju GouStephen SalernoLiang MaPing FuBackground: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. Methods: C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. Results: In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-α, IL-6, and IL-1β) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-κB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01). Conclusion: The pharmacological inhibition of TLR4/NF-κB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.http://www.cmj.org/article.asp?issn=0366-6999;year=2017;volume=130;issue=18;spage=2163;epage=2169;aulast=HuangAcute Kidney Injury; Macrophages; Rhabdomyolysis; Toll-Like Receptor 4; NF-kappa B |
| spellingShingle | Rong-Shuang Huang Jiao-Jiao Zhou Yu-Ying Feng Min Shi Fan Guo Shen-Ju Gou Stephen Salerno Liang Ma Ping Fu Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury Chinese Medical Journal Acute Kidney Injury; Macrophages; Rhabdomyolysis; Toll-Like Receptor 4; NF-kappa B |
| title | Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury |
| title_full | Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury |
| title_fullStr | Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury |
| title_full_unstemmed | Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury |
| title_short | Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury |
| title_sort | pharmacological inhibition of macrophage toll like receptor 4 nuclear factor kappa b alleviates rhabdomyolysis induced acute kidney injury |
| topic | Acute Kidney Injury; Macrophages; Rhabdomyolysis; Toll-Like Receptor 4; NF-kappa B |
| url | http://www.cmj.org/article.asp?issn=0366-6999;year=2017;volume=130;issue=18;spage=2163;epage=2169;aulast=Huang |
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