Increased Expression of Toll-Like Receptor 2 in Rat Diabetic Nephropathy

Li, Fanglin; Yang, Niansheng; Zhang, Lili; Tan, Hongna; Huang, Bin; Liang, Yingjie; Chen, Miaoyan; Yu, Xueqing

doi:10.1159/000317023

Cited by 53 publications

(50 citation statements)

References 45 publications

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“…There is an increase in the expression of TLR2 in the tubules and an upregulation of nuclear and cytoplasmic staining of HMGB1 in STZ-induced diabetic kidneys. This is consistent with the findings of Li et al (23), who demonstrate an upregulation of renal TLR2 in diabetic rats and human biopsy samples. Taken together, this suggests that TLR2 may be the integral receptor in transducing inflammation in diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 93%

“…Although Lin et al did not study TLR2 expression in their diabetic in vivo model, they showed that TLR4 cortical expression in their diabetic animals was not significantly different from the wild-type controls, which is consistent with our data shown here. This is consistent with a recent study which showed prominent expression of TLR2 in the kidneys of diabetic rats with an associated increase in inflammatory infiltration (23). To date, enhanced expression of TLRs and downstream proinflammatory markers studied in in vivo models have been usually attributed to the increase in infiltrating immune cells, including the study by Devaraj et al (10), who discussed the increase in TLR2 expres- sion and its signal transduction in peritoneal and kidney macrophages.…”

Section: Discussionsupporting

confidence: 91%

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The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

Mudaliar

Pollock

Komala

et al. 2013

American Journal of Physiology-Renal Physiology

116

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Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

Mudaliar

Pollock

Komala

et al. 2013

American Journal of Physiology-Renal Physiology

116

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“…and micro-and macrovascular complications as well as markers of LGI and ED in patients with type 1 diabetes. The positive association between HMGB1 and albuminuria observed in this study is supported by the findings in previous studies on rats, in which higher kidney HMGB1 levels were associated with the presence and severity of diabetic nephropathy (39). In addition, it has been reported that higher HMGB1 expression was found in the cytoplasm than in the nuclei of renal tissues in diabetic rats compared with mainly nucleic HMGB1 expression in renal tissues in control rats (21).…”

Section: Discussionsupporting

confidence: 91%

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Nin¹,

Ferreira²,

Schalkwijk³

et al. 2012

European Journal of Endocrinology

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Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40G10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised bZ0.07 (95% confidence interval (CI): 0.02-0.12) and bZ0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro-and macroalbuminuria: odds ratio (OR)Z1.24 (95% CI: 0.90-1.71) and ORZ1.61 (95% CI: 1.15-2.25) respectively, P for trendZ0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.

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“…However, they did not report on podocyte function or mesangial expansion. In contrast, Li et al (30) reported increased TLR2 expression in renal TEC in human renal biopsy DN samples as well as in kidneys of rat models of DN. However, various other reports have also provided evidence of TLR4 association in glomerular injury in DN (2,29,34).…”

Section: Discussionmentioning

confidence: 83%

Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy

Kaur

Chien

Jialal

2012

American Journal of Physiology-Renal Physiology

104

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Diabetes is a proinflammatory state. The pattern recognition receptors, Toll-like receptors (TLRs), are increased in diabetic patients and have been suggested to play a role in diabetic nephropathy (DN). Progression of DN involves altered mesangial cell (MC) function with an expansion of the mesangial matrix. There is a paucity of data examining the role of TLR and its expression in MC. We hypothesize the expression of TLRs in the mesangium might be an important factor contributing to mesangium expansion and nephropathy. Thus we evaluated the effect of high glucose on TLR2 and TLR4 expression in mouse mesangial cells (MMC) in vitro. Exposure of MMC to 25 mM glucose for 24 h resulted in increased TLR4 mRNA and cell surface receptor expression compared with 5.5 mM glucose (P < 0.05). Interestingly, we were not able to detect expression of TLR2 in MMC. Furthermore, expression of a TLR4 downstream signaling cascade including myeloid differentiation factor 88 (MyD88), interferon regulatory factor 3 (IRF3), and Toll interleukin receptor domain containing adaptor inducing interferon-β (TRIF)-related adaptor molecule (TRAM) were significantly increased in cells exposed to 25 mM glucose (P < 0.05). There was also a significant increase in NF-κB activation along with increased secretion of inflammatory cytokines IL-6 and monocyte chemotactic protein-1. Levels of transforming growth factor-β were also significantly increased in the presence of 25 mM glucose (P < 0.05). Collectively, these data suggest that hyperglycemia activates TLR4 expression and activity in MC and could contribute to DN.

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Increased Expression of Toll-Like Receptor 2 in Rat Diabetic Nephropathy

Cited by 53 publications

References 45 publications

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy

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