Toll-like receptors: sensing and reacting to diabetic injury in the kidney

Accumulating evidence indicates that immunologic and inflammatory elements play an important role in initiating and orchestrating the development of diabetic nephropathy (DN), but until recently, the identity of specific innate immune pattern recognition receptors or sensors that recognize diverse diabetic 'danger signals' to trigger the proinflammatory cascade during DN remains unknown. Toll-like receptors (TLRs) are an emerging family of receptors that recognize pathogen-associated molecular patterns as well as damage-associated molecular patterns to promote the activation of leukocytes and intrinsic renal cells in non-immune kidney disease. Recent data from in vitro and in vivo studies have highlighted the critical role of TLRs, mainly TLR2 and TLR4, in the pathogenesis of DN. This review focuses on emerging findings elucidating how TLR signaling could sense and react to the metabolic stress and endogenous ligands activated by the diabetic state, thereby initiating and perpetuating renal inflammation and fibrogenesis in diabetic kidney disease. Novel strategies potentially targeting TLR signaling that could have therapeutic implications in DN are also discussed.