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Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury.
Huang, Rong-Shuang; Zhou, Jiao-Jiao; Feng, Yu-Ying; Shi, Min; Guo, Fan; Gou, Shen-Ju; Salerno, Stephen; Ma, Liang; Fu, Ping.
Affiliation
  • Huang RS; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Zhou JJ; Division of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Feng YY; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Shi M; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Guo F; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Gou SJ; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Salerno S; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Ma L; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
  • Fu P; Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Chin Med J (Engl) ; 130(18): 2163-2169, 2017 Sep 20.
Article in En | MEDLINE | ID: mdl-28836571
ABSTRACT

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)-1ß 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-1ß) 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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rhabdomyolysis / NF-kappa B / Toll-Like Receptor 4 / Acute Kidney Injury Type of study: Prognostic_studies Limits: Animals Language: En Journal: Chin Med J (Engl) Year: 2017 Document type: Article Affiliation country: China

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rhabdomyolysis / NF-kappa B / Toll-Like Receptor 4 / Acute Kidney Injury Type of study: Prognostic_studies Limits: Animals Language: En Journal: Chin Med J (Engl) Year: 2017 Document type: Article Affiliation country: China