AsianScientist (Jun. 29, 2015) – A high-sugar and high-fat diet hyperactivates the innate immune system, resulting in inflammation-driven damage to the kidneys. The study documenting these findings, published in Science Advances, used miniature pigs, a model organism which mimics the human system more closely than mice and other commonly used animals.
Diabetic nephropathy (DN) is among the most common complications of diabetes mellitus and a main cause of renal failure. Despite the high economic burden of DN, exactly how diabetes causes DN remains unclear. Recent studies have suggested that excess nutrient molecules such as fatty acids and glucose can activate the innate immune system, giving rise to a low-grade, chronic inflammation known as metabolic inflammation.
In the present study, a team of researchers from Chinese People’s Liberation Army (PLA) General Hospital led by Professors Chen Xiangmei and Bai Xue-Yuan investigated the role of innate immune receptors known as the Toll-like receptor (TLR) system in a mini-pig model of diabetes.
“In recent years, rodent models of diabetes have been established. However, because there are considerable differences between rodents and human with respect to genetics, anatomy, physiology, and metabolism, research findings based on rodents can not well simulate the pathogenic processes of human disease,” Chen and Bai told Asian Scientist Magazine.
“Importantly, humans and mice were found to differ significantly with respect to immune inflammatory system, including the TLR system and inflammatory responses.”
After the Chinese Bama mini-pigs were fed a high-sugar and high-fat diet for eight months, they showed diabetes-like symptoms with elevated levels of fasting blood glucose and insulin.
“We found that overnutrition can significantly activate and promote the expression of the molecules in the TLR signaling pathway, including MyD88-dependent TLR2, 4, 5, 7, 8, 11, MyD88 and IRAK-1, as well as MyD88-independent TLR3-4 and IRF-3. Overnutrition also prominently activated the molecules in the downstream NF-κB signaling pathway, including IKKβ, IκBα and NF-κBp65,” they said.
The researchers also found that diabetics pigs expressed higher levels of inflammatory factors such as IL-6, MIP-2, MCP-1, CCL5 and VCAM-1. Diabetic big kidneys stained positive for CD68, indicating active macrophage infiltration, a sign of chronic inflammation.
Based on these findings, the researchers suggest that drugs targeting the TLR signalling pathway could potentially be used to prevent diabetic renal injuries.
“Although animal experiments have shown that the blockade of TLR4 or TLR2 ameliorated other renal injury, to date, there are no approved therapeutic agents targeting TLRs that have been shown to play a pivotal role in initiating and propagating persistent inflammation in diabetes kidneys,” Chen and Bai noted.
“In future research, we hope to investigate treatment effect of TLRs antagonists for diabetic injury.”
The article can be found at: Feng et al. (2015) Role of Toll-Like Receptors in Diabetic Renal Lesions in a Miniature Pig Model.
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Copyright: Asian Scientist Magazine; Photo: Chen Xiangmei and Bai Xue-Yuan/Chinese PLA General Hospital.
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