Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet

Hye Sook Min, Jung Eun Kim, Mi Hwa Lee, Hye Kyoung Song, Mi Jin Lee, Ji Eun Lee, Hyun Wook Kim, Jin Joo Cha, Young Youl Hyun, Jee Young Han, Dae-Ryong Cha, Young Sun Kang

Research output: Contribution to journalArticle

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Abstract

Background Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor α [as well as interleukin (IL)-1β, IL-10, and interferon γ]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). Methods Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). Results Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. Conclusion TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

Original languageEnglish
Pages (from-to)33-44
Number of pages12
JournalKidney Research and Clinical Practice
Volume33
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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Toll-Like Receptor 4
Kidney Diseases
High Fat Diet
Acetic Acid
Toll-Like Receptors
Obesity
Oxidative Stress
Cytokines
Obese Mice
Soybean Oil
Glucose Intolerance
3-phenyl-4,5-dihydro-5-isoxazole acetic acid
Interleukin-1
Inbred C57BL Mouse
Lipid Metabolism
Innate Immunity
Interleukin-10
Interferons
Extracellular Matrix
Adipose Tissue

Keywords

  • Kidney disease
  • Metabolic syndrome
  • Obesity
  • Toll-like receptors

ASJC Scopus subject areas

  • Nephrology
  • Urology

Cite this

Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet. / Min, Hye Sook; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Lee, Mi Jin; Lee, Ji Eun; Kim, Hyun Wook; Cha, Jin Joo; Hyun, Young Youl; Han, Jee Young; Cha, Dae-Ryong; Kang, Young Sun.

In: Kidney Research and Clinical Practice, Vol. 33, No. 1, 01.01.2014, p. 33-44.

Research output: Contribution to journalArticle

Min, Hye Sook ; Kim, Jung Eun ; Lee, Mi Hwa ; Song, Hye Kyoung ; Lee, Mi Jin ; Lee, Ji Eun ; Kim, Hyun Wook ; Cha, Jin Joo ; Hyun, Young Youl ; Han, Jee Young ; Cha, Dae-Ryong ; Kang, Young Sun. / Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet. In: Kidney Research and Clinical Practice. 2014 ; Vol. 33, No. 1. pp. 33-44.
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abstract = "Background Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor α [as well as interleukin (IL)-1β, IL-10, and interferon γ]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). Methods Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60{\%} of total calories from fat, 5.5{\%} from soybean oil, and 54.5{\%} from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). Results Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. Conclusion TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.",
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T1 - Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet

AU - Min, Hye Sook

AU - Kim, Jung Eun

AU - Lee, Mi Hwa

AU - Song, Hye Kyoung

AU - Lee, Mi Jin

AU - Lee, Ji Eun

AU - Kim, Hyun Wook

AU - Cha, Jin Joo

AU - Hyun, Young Youl

AU - Han, Jee Young

AU - Cha, Dae-Ryong

AU - Kang, Young Sun

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor α [as well as interleukin (IL)-1β, IL-10, and interferon γ]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). Methods Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). Results Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. Conclusion TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

AB - Background Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor α [as well as interleukin (IL)-1β, IL-10, and interferon γ]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). Methods Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). Results Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. Conclusion TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

KW - Kidney disease

KW - Metabolic syndrome

KW - Obesity

KW - Toll-like receptors

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