Targeting innate immunity as therapeutic strategy in diabetic nephropathy

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Título:
Targeting innate immunity as therapeutic strategy in diabetic nephropathy
Autor: Chen, Xiaochen
Assuntos: diabetic nephropathy ; HMGB1 ; kidney disease ; RAGE ; SCFA ; TLR
Descrição: Diabetic nephropathy (DN) is the most common cause of both chronic kidney disease and end-stage kidney disease worldwide, which affects 30-40% of people with Type 1 or Type 2 diabetes. DN was initially considered to be a non-immune kidney disease, but accumulating evidence suggests that sterile inflammatory processes induced by innate immunity play significant roles in the development and progression of DN. Although reasonable therapeutic strategies are taken to prevent the progression of DN, the burden of DN continue to increase. The aim of this study was to explore novel therapeutic strategies to treat DN by targeting innate immunity and investigate the underlying mechanisms.«br /» «br /» Toll like receptors (TLRs) are germline-encoded innate immune receptors expressed by both immune cells, such as macrophages, monocytes, dendritic cells and lymphocytes; and non-immune cells, including kidney tubular epithelial cells and podocytes. TLRs can recognise not only exogenous ligands by the specific molecular patterns that are present on microorganisms, but also endogenous ligands released from damaged tissue, known as damage-associated molecular patterns (DAMPs). DAMP, such as high mobility group box 1 (HMGB1), induced TLRs activation is considered as a potential cause of sterile inflammation leading to diabetic nephropathy. HMGB1 can be recognised by not only TLR2 and TLR4, but also the receptor for advanced glycation end-products (RAGE), a well-established mediator of DN. Thus, in this study, the first two therapeutic strategies were used to inhibit interactions between HMGB1 and its receptors (TLRs or RAGE) by systemic overexpression of endogenous secretory RAGE (esRAGE), a soluble decoy receptor for HMGB1, or administration of recombinant HMGB1 A Box, a specific competitive antagonist for HMGB1. These two therapeutic strategies significantly attenuated diabetic kidney injury and the local inflammatory response. Further investigation of the effectiveness of esRAGE in TLR2, TLR4 or RAGE knockout diabetic mice was then performed. TLR2 knockout mice, known to be partially protected from the development of DN, received further protection against DN by systemic overexpression of esRAGE, whereas TLR4 and RAGE deficient mice did not, suggesting TLR4 and RAGE pathways are the key target of esRAGE.«br /» «br /» Short chain fatty acids (SCFAs) are produced by the intestinal microbiota during the fermentation of dietary fibre and exert profound effects on immune responses and inflammation. The administration of SCFAs have been found to attenuated numerous inflammatory diseases, including inflammatory bowel disease (IBD), sepsis, acute lung injury and ischemia induced injury. In this thesis, the third therapeutic intervention in DN was the administration of SCFAs. Here we found the SCFA acetate to protect against DN when administered IP and/or orally. Much ongoing work is required to understand the mechanism of this protection, however my observations within this thesis suggest a significant protection against the development of DN.«br /» «br /» In summary, systemic overexpression of esRAGE was successful in attenuating kidney inflammation and damage in experimental models of DN. Effects were mediated by TLR4 and RAGE pathways. Treatment with HMGB1 A Box to specifically inhibit HMGB1 activity provided the protection in DN, confirming a pathogenic role for HMGB1 in diabetic nephropathy and confirming a potential therapeutic role for HMGB1 blockade in preventing the progression of DN. The administration of SCFAs attenuated the development of DN raising the attentive possibility of dietary strategies to treat DN. Collectively, the three strategies tested in this thesis identify new therapeutic targets in DN, which, once further evaluated, may lead to exciting new treatments for the enormous problem of DN in man.«br /» Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.
Editor: Central Clinical School
Data de criação/publicação: 2017
Idioma: Inglês

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Targeting innate immunity as therapeutic strategy in diabetic nephropathy

Chen, Xiaochen

Central Clinical School 2017

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