Abstract
Activation of TLR2 or TLR4 by endogenous ligands such as high mobility group box 1 (HMGB1) may mediate inflammation causing diabetic kidney injury. We determined whether blockade of HMGB1 signaling by: (1) supra-physiological production of endogenous secretory Receptor for Advanced Glycation End-products (esRAGE), a receptor for HMGB1; (2) administration of HMGB1 A Box, a specific competitive antagonist, would inhibit development of streptozotocin induced diabetic nephropathy (DN). Wild-type diabetic mice developed albuminuria, glomerular injuries, interstitial fibrosis and renal inflammation. Using an adeno-associated virus vector, systemic over-expression of esRAGE afforded significant protection from all parameters. No protection was achieved by a control vector which expressed human serum albumin. Administration of A Box was similarly protective against development of DN. To determine the mechanism(s) of protection, we found that whilst deficiency of TLR2, TLR4 or RAGE afforded partial protection from development of DN, over-expression of esRAGE provided additional protection in TLR2−/−, modest protection against podocyte damage only in TLR4−/− and no protection in RAGE−/− diabetic mice, suggesting the protection provided by esRAGE was primarily through interruption of RAGE and TLR4 pathways. We conclude that strategies to block the interaction between HMGB1 and its receptors may be effective in preventing the development of DN.
Highlights
Diabetic nephropathy (DN) develops in 30–40% of people with Type 1 or 2 diabetes and has become the most frequent cause of end-stage renal disease[1,2]
Declining levels seen between 6 weeks and three months are most likely the inevitable consequence of continuing hepatocyte turnover. endogenous secretory Receptor for Advanced Glycation End-products (esRAGE) construct binding to high mobility group box 1 (HMGB1) was confirmed by co-immuno-precipitation and western blot (Fig. 1c)
Activation of the innate immune system by endogenous HMGB1 required TLR4 or RAGE signaling, consistent with previous observations that TLR4−/− mice or RAGE−/− were partially protected against diabetic nephropathy (DN)
Summary
Diabetic nephropathy (DN) develops in 30–40% of people with Type 1 or 2 diabetes and has become the most frequent cause of end-stage renal disease[1,2]. Evidence from clinical and experimental studies has demonstrated that sterile inflammatory processes triggered by innate immune responses via TLRs and RAGE play vital roles in the pathogenesis and progression of DN3–7. TLR2 and 4 activation by endogenous ligands including high mobility group box 1 (HMGB1), heat-shock proteins (HSPs) and biglycan, leads to translocation of NF-κB9 with consequent upregulation of pro-inflammatory cytokines (TNFα & IL6) and chemokines (CCL2), triggering a sterile inflammation as known to participate in the pathogenesis of DN10–13. We have found that in vitro, high glucose promotes release of endogenous TLR ligands, including HMGB1, by tubular epithelial cells and podocytes, which coupled with upregulation of TLR2 and 4, resulted in activation of NF-κB and consequent production of pro-inflammatory cytokines[5,6,7]. Over-expression of esRAGE to generate supra-physiological concentrations in blood has potential to prevent RAGE, and TLR2 and 4, engagement and activation by soluble ligands such as HMGB118,19
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