Diabetic Nephropathy: Role of Toll-like Receptors and Notch Pathway

Diabetes mellitus is a chronic endocrine disease distinguished by hyperglycemia because of deregulations of carbohydrate or lipid metabolism or insulin function. The chronic hyperglycemic condition of the disease is correlated with relatively specific long-lasting microvascular and macrovascular complications. Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease inthe United States and most developed countries. Diabetes accounts for 30% to 50% of the incidentcases of end-stage kidney disease in the United States. Although this represents a significant publichealth concern, it is important to note that only 30% to 40% of patients with diabetes develop diabeticnephropathy. This book has been written with the basic concept ofnew approach of diabeticnephropathymanagements. Over the past decade, a large body of research has focused on diabeticnephropathy ranging from studies in molecular signaling, hemodynamic regulation and pharmaceutical intervention to clinicaloutcomes. It is likely that the pathophysiology of diabetic nephropathy involves a multifactorial interaction between metabolic andhemodynamic factors. Metabolic factors involve glucose-dependent pathways, such as advanced glycation end-products and theirreceptors. Hemodynamic factors include various vasoactive hormones, such as components of the renin–angiotensin system. Specific inhibitors of the various pathways are now available and these emerging pharmaceutical interventionsmight have potential implications for the prevention and treatment of diabetic nephropathy. The mainstay of therapy remains theachievement of optimal glycemic and blood pressure control in order to slow the progression of diabetic nephropathy. Toll-like receptors are transmembrane proteins that transfer the antigen recognition information from outside to inside of the cell as a factor in the immune reaction. Activation of the innate immune system via TLRs is implicated in the pathogenesis of insulin resistance, diabetic nephropathy, and atherosclerosis.TLR2 and/or TLR4 might be a molecular linkbetween inflammation and diabetes mellitus as they promote tubulointerstitialinflammation during diabetic nephropathy. TLR4 has amajor role in renal inflammation and progressive fibrosis in kidney disease, modulating these TLRs could be helpful in preventing complications of diabetes mellitusgiving the keyrole of inflammation in both microvascular and macrovascular complications. Notch signalling is a highly conserved cell–cell communication mechanism that regulates development, tissuehomeostasis, and repair. Within the kidney, Notch has an important function in orchestrating kidney development.Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephronsegmentation as well as the differentiation of principal cells in the renal collecting system. Notch signalling is markedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute andchronic kidney injuries. Increased glomerular epithelial Notch signalling has been associated with albuminuria andglomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducing an improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidneydevelopment, repair, and injury.