ISBN 978-93-5547-365-3 (Print)
ISBN 978-93-5547-373-8 (eBook)
DOI: 10.9734/bpi/mono/978-93-5547-365-3

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.

Media Promotion

### Content

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

Diabetic Nephropathy: Role of Toll-like Receptors and Notch Pathway, 5 January 2022, Page 1
https://doi.org/10.9734/bpi/mono/978-93-5547-365-3/CH0

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.

##### Pathophysiology of Diabetic Nephropathy

Diabetic Nephropathy: Role of Toll-like Receptors and Notch Pathway, 5 January 2022, Page 2-23
https://doi.org/10.9734/bpi/mono/978-93-5547-365-3/CH1

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).

##### Toll-like Receptors: Sensing and Reacting to Diabetic Injury in the Kidney

Diabetic Nephropathy: Role of Toll-like Receptors and Notch Pathway, 5 January 2022, Page 24-48
https://doi.org/10.9734/bpi/mono/978-93-5547-365-3/CH2

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.