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

Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The intended aim during the management of diabetes is to maintain blood glucose close to normal because the majority of patients have poor control of their elevated blood glucose and are highly prone to severe macrovascular and microvascular complications. 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 toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance, diabetic nephropathy, and atherosclerosis. 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 and chronic kidney injuries. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, 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 kidney development, repair, and injury.

Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processesare interwoven and present two sides of one coin. On a molecular level, hyperglycaemia andproteins altered by high blood glucose such as Amadori products and advanced glycationend-products (AGEs) are key players in the development of diabetic nephropathy. Recentevidence suggests that an increase in reactive oxygen species (ROS) formation induced byhigh glucose-mediated activation of the mitochondrial electron-transport chain is an earlyevent in the development of diabetic complications. A variety of growth factors and cytokinesare then induced through complex signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-_KB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines, particularly, TGF-\(\beta\)isimportant in the development of renal hypertrophy and accumulation of extracellular matrixcomponents. Activation of the renin-angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes manyof the pathophysiological changes associated with diabetic nephropathy. In fact, it has beenshown that angiotensin II is involved in almost every pathophysiological process implicatedin the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellularmatrix accumulation, growth factor/cytokine induction, ROS formation, podocytedamage, proteinuria, interstitial inflammation).

Diabetes mellitus (DM) is a chronic endocrine disease distinguished by hyperglycemia due to disturbance in carbohydrate or lipid metabolism or insulin function. To date, diabetes, and its complications, is established as a global cause of morbidity and mortality. The intended aim during the management of diabetes is to maintain blood glucose close to normal because the majority of patients have poor control of their elevated blood glucose and are highly prone to severe macrovascular and microvascular complications. To decrease the burden of the disease and its complications, scientists from various disciplines are working intensively to identify novel and promising drug targets for diabetes and its complications. Innate immunity plays a crucial role in the pathogenesis of type 2 diabetes andrelated complications. Since the toll-like receptors (TLRs) are central to innateimmunity, it appears that they are important participants in the development andpathogenesis of the disease. Previous investigations demonstrated that TLR2 homodimers and TLR2 heterodimers with TLR1 or TLR6 activate innate immunityupon recognition of damage-associated molecular patterns (DAMPs). Accumulating evidence indicates that immunologic and inflammatoryelements play an important role in initiating and orchestratingthe development of diabetic nephropathy (DN), but untilrecently, the identity of specific innate immune pattern recognitionreceptors or sensors that recognize diverse diabetic‘danger signals’ to trigger the proinflammatory cascade duringDN remains unknown. Toll-like receptors (TLRs) are an emergingfamily of receptors that recognize pathogen-associated molecularpatterns as well as damage-associated molecular patternsto promote the activation of leukocytes and intrinsic renal cellsin non-immune kidney disease. Recent data from in vitro and invivo studies have highlighted the critical role of TLRs, mainlyTLR2 and TLR4, in the pathogenesis of DN.

Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated indiabetic nephropathy in vitro and in vivo. 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 ismarkedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute andchronic kidney injury. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducingan improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidney development, repair, and injury. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. A ngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. Incultured human tubular epithelial cells, the Notch activation by transforming growth factor-b1 (TGF-b1) has been involved inepithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-b1.