Abstract
Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4−/− mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.
Highlights
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease globally and continues to grow in incidence and prevalence in parallel with the pandemic of type 2 diabetes [1]
Immunohistochemistry staining indicated upregulation of TLR4 protein in tubules and glomeruli consistent with a podocyte distributionin with DN (WT-DN) (Figure 2C). mRNA expression of endogenous ligands including HSP70, high-mobility group box 1 (HMGB1) and biglycan were up-regulated in WT-DN (Figure 2B)
Albuminuria was halved in TLR42/2 mice with DN compared to WT-DN at all time points (Figure 3)
Summary
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease globally and continues to grow in incidence and prevalence in parallel with the pandemic of type 2 diabetes [1]. Between 20–40% of those with diabetes develop progressive nephropathy leading to stage 5 chronic kidney disease. Historically considered as a largely ‘non-inflammatory’ disease process, emerging evidence from experimental and clinical studies has indicated that inflammatory processes facilitated by innate immune responses play a significant role in the development and progression of DN [2,3]. Upon activation TLRs signal via an adaptor molecule MyD88, leading to translocation of nuclear factor kappa B (NF-kB) with consequent upregulation of pro-inflammatory cytokines and chemokines, in turn initiating local inflammation and leukocyte accumulation
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