Kidney Res Clin Pract.  2014 Mar;33(1):33-44.

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 HS
• Kim JE
• Lee MH
• Song HK
• Lee MJ
• Lee JE
• Kim HW
• Cha JJ
• Hyun YY
• Han JY
• Cha DR
• Kang YS

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 alpha [as well as interleukin (IL)-1beta, IL-10, and interferon gamma]. 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.

Keyword

Kidney disease; Metabolic syndrome; Obesity; Toll-likereceptors

MeSH Terms

Acetic Acid*
Adipose Tissue
Animals
Cytokines
Diet
Diet, High-Fat*
Extracellular Matrix
Fibrosis
Glucose Intolerance
Humans
Immune System
Immunity, Innate
Inflammation
Interferons
Interleukin-10
Interleukins
Kidney
Kidney Diseases*
Lipid Metabolism
Macrophages
Male
Mice*
Mice, Obese
Obesity
Oxidative Stress
Soybean Oil
Toll-Like Receptors*
Tumor Necrosis Factor-alpha
Acetic Acid
Cytokines
Interferons
Interleukin-10
Interleukins
Soybean Oil
Toll-Like Receptors
Tumor Necrosis Factor-alpha