Role of Toll-like receptors in diabetic renal lesions in a miniature pig model

文献类型： 外文期刊

第一作者： Feng, Yuanyuan

作者： Feng, Yuanyuan;Ma, Yuxiang;Bai, Xue-Yuan;Chen, Xiangmei;Yang, Shulin

作者机构：

期刊名称：SCIENCE ADVANCES （ 影响因子：14.136； 五年影响因子：16.446 ）

ISSN： 2375-2548

年卷期： 2015 年 1 卷 5 期

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收录情况： SCI

摘要： The mechanisms of diabetic renal injury remain unclear. Recent studies have shown that immunological and inflammatory elements play important roles in the initiation and development of diabetic nephropathy (DN). Toll-like receptors (TLRs) comprise a superfamily of innate immune system receptors. The roles and mechanisms of TLRs in the pathogenesis of diabetic renal lesions are mostly unknown. Compared with rodents, miniature pigs are more similar to humans with respect to metabolism, kidney structure, and immune system, and therefore represent an ideal large-animal model for DN mechanistic studies. A diabetes model was established by feeding miniature pigs with high-sugar and high-fat diets. Functional and pathological markers, expression and activation of endogenous TLR ligands [HSP70 (heat shock protein 70) and HMGB1], TLR1 to TLR11 and their downstream signaling pathway molecules (MyD88, IRAK-1, and IRF-3), nuclear factor kappa B (NF-kappa B) signaling pathway molecules (IKK beta, I kappa B alpha, and NF-kappa Bp65), inflammatory cytokines [IL-6 (interleukin-6), MIP-2, MCP-1, CCL5, and VCAM-1 (vascular cell adhesion molecule-1)], and infiltration of inflammatory cells were systematically evaluated. The expression of HSP70 was significantly increased in diabetic pig kidneys. The expression of MyD88-dependent TLR2, TLR4, TLR5, TLR7, TLR8, and TLR11 and their downstream signalingmolecules MyD88 and phospho-IRAK-1 (activated IRAK-1), as well as that of MyD88-independent TLR3 and TLR4 and their downstream signaling molecule phospho-IRF-3 (activated IRF-3), was significantly up-regulated. The expression and activation of NF-kappa B pathway molecules phospho-IKK beta, phospho-I kappa B alpha, NF-kappa Bp65, and phospho-NF-kappa Bp65 were significantly increased. Levels of IL-6, MIP-2, MCP-1, CCL5, VCAM-1, and macrophage marker CD68 were significantly increased in diabetic pig kidneys. These results suggested that the metabolic inflammation activated by TLRs might play an important role in diabetic renal injuries.

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