title: Role of Toll-like receptors in diabetic renal lesions in a miniature pig model.
abstract: 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 κB (NF-κB) signaling pathway molecules (IKKβ, IκBα, and NF-κBp65), 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 signaling molecules 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-κB pathway molecules phospho-IKKβ, phospho-IκBα, NF-κBp65, and phospho-NF-κBp65 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.
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Key Laboratory for Farm Animal Genetic Resources and Utilization of Ministry of Agriculture of China, Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing 100193, China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Bai
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
keywords: Diabetic nephropathy; Toll-like receptors (TLRs); innate immune; metabolic inflammation; miniature pigs