esRAGE: A new therapeutic approach to diabetic nephropathy?

Messchendorp, A.L. (2013) esRAGE: A new therapeutic approach to diabetic nephropathy? thesis, Medicine.

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Abstract

In diabetic subjects advanced glycation end products (AGEs) are formed because of high blood glucose levels. AGEs can trigger their receptor, RAGE, to initiate an inflammatory cascade which leads to diabetic nephropathy (DN). High mobility group box 1 (HMGB1) is a damage associated molecular pattern (DAMP), released from damaged cells and activated cells of the immune system. HMGB1 can also trigger an inflammatory cascade through toll-like receptor (TLR) 2, TLR4 and RAGE. Soluble forms of RAGE, soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are able to act as a decoy receptor and prevent the inflammatory cascade. Previous research conducted by our research group found protective effects of esRAGE on the development of DN. In this study, we sought to determine whether the protective effects of esRAGE are mediated by blockade of HMGB1 signalling through TLR2. TLR2-/- mice received either an intraperitoneal (IP) injection with 55mg/kg streptozotocin (STZ) (n=13) or an IP injection with citrate buffer as controls (n=5). After 2 weeks mice receiving an STZ injection developed diabetes and were given an IP injection either with 5x1011 vector encoding recombinant adeno-associated virus (rAAV) esRAGE (TLR2-/- D esRAGE n=7) or 5x1011 vector encoding and rAAV-Human serum albumin (HSA) (TLR2-/- D HSA n=6). Ten weeks after viral injection urine was collected for the assessment of albuminuria and mice were sacrificed. Kidneys were examined for glomerular hypertrophy, glomerular hyperplasia and interstitial fibrosis. Data are expressed as the mean ± SD and analysed by ANOVA or t-test. All p-values of ≤0.05 were considered significant. The development of albuminuria in TLR2-/- mice with diabetes was not affected by esRAGE (urine albumin-creatinin ratio 145.7±29.18 vs. 121.2±26.53 mg/mmol, p=0.43, for TLR2-/- D esRAGE vs HSA). Treated mice did show a reduction in glomerular volume expansion (181178±14767 vs. 152900±22411 μm3, p=0.029) and interstitial fibrosis (11.97±1.55 vs. 8.87±0.63 %, p=0.003) and non-significant trends towards reduced kidney to bodyweight ratio (18.57±2.83 vs. 21.47±1.19 mg/g, p=0.0501)and glomerular hypercellularity. In conclusion, viral expression of esRAGE provided modest protection against the development of DN in TLR2-/- mice with STZ diabetes, suggesting that the benefits of esRAGE expression observed in WT diabetic mice cannot solely be attributed to inhibition of TLR2 pathway signalling. Further studies are underway to determine the dominant pathway.

Item Type:	Thesis (Thesis)
Supervisor name:	Son, Prof. Dr. W.J. van
Supervisor name:	Chadban, Prof. Dr. S.J. and Royal Prince Alfred Hospital & University of Sydney, Austral and Wu, Dr. H. and Collaborative Transplant Research Group and Sydney, Australia
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:58
Last Modified:	25 Jun 2020 10:58
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1833

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