Toll-like Receptor-4 Signaling Mediates Inflammation and Tissue Injury in Diabetic Nephropathy

Toll-like receptors (TLRs) are a class of receptors of the innate immune system which detect pathogen-associated and danger-associated molecular patterns in order to initiate an inflammatory response. TLR2 and TLR4 downward signaling causes the production of proinflammatory cytokines that can induce insulin resistance and cardiovascular damage in obesity and type 2 diabetes mellitus. In diabetic nephropathy, TLR4, nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and NLRP3 inflammasome are involved in the production and persistence of inflammation. The activation of TLRs stimulates the expression of several inflammatory cytokines and chemokines such as CCL2 and tumor necrosis factor (TNF)-α, which are associated with the progression of diabetic nephropathy. Different inflammatory mechanisms seem to take place in the early and late stages of diabetic kidney disease, with activation of the innate immunity response and enhanced chemiotactic effects in native kidney cells at an early stage, followed by tubulointerstitial monocyte infiltration at a more advanced disease state. Overall, available data indicate that the upregulated TLR4 response in the kidney translates the metabolic alterations of diabetes into kidney damage.