Molecular signaling pathways of diabetic kidney disease; new concepts (original) (raw)
Related papers
Diabetic kidney disease is a main cause of end-stage renal disease (ESRD), therefore, it is important to understand the molecular mechanism underlying diabetic kidney disease. Todays, various factors such as hemodynamic changes, molecular signaling and metabolic pathways have been shown to be involved in its pathogenesis. Excessive glucose influx stimulates cellular signaling pathways, containing advanced glycation end-products (AGEs), oxidative stress conditions, Rho-kinase, the diacylglycerol (DAG)-protein kinase C (PKC) pathway, polyol pathway and hexosamine pathway. In hyperglycemic condition, these factors cooperate with other aggravating factors. Then activated inflammatory processes lead to the development of glomerulosclerosis. The aim is to describe understanding of the signaling pathways in diabetic kidney disease.
Molecular Mechanisms in Early Diabetic Kidney Disease: Glomerular Endothelial Cell Dysfunction
International Journal of Molecular Sciences
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), with prevalence increasing at an alarming rate worldwide and today, there are no known cures. The pathogenesis of DKD is complex, influenced by genetics and the environment. However, the underlying molecular mechanisms that contribute to DKD risk in about one-third of diabetics are still poorly understood. The early stage of DKD is characterized by glomerular hyperfiltration, hypertrophy, podocyte injury and depletion. Recent evidence of glomerular endothelial cell injury at the early stage of DKD has been suggested to be critical in the pathological process and has highlighted the importance of glomerular intercellular crosstalk. A potential mechanism may include reactive oxygen species (ROS), which play a direct role in diabetes and its complications. In this review, we discuss different cellular sources of ROS in diabetes and a new emerging paradigm of endothelial cell dysfunction as a key event...
Review on pathophysiology and treatment of diabetic kidney disease
Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 2010
Diabetes is the leading cause of chronic kidney disease, which in the Thailand is the most common cause of end stage renal disease (ESRD) requiring dialysis. Patients with diabetic kidney disease (DKD) are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes. The development of DKD is determined by environmental and genetic factors. This review focuses on the latest published data dealing with mechanisms and treatment of DKD. DKD has several distinct phases of development of the disease and hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney disease. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage: nonenzymatic glycosylation that generates advanced glycosylation end products, activation of protein kinase C, and acceleration of the polyol pathway. Oxidative stress also seems to be a theme common pathway. These derangements, along w...
Pathophysiology of Diabetic Nephropathy: Involvement of Multifaceted Signalling Mechanism
Journal of Cardiovascular Pharmacology, 2009
Diabetic nephropathy is a major cause of end-stage renal failure and the mortality rate due to this disease is continuously progressing worldwide. The multifaceted signalling mechanisms have been identified to be involved in the pathogenesis of diabetic nephropathy. Despite the modern therapies like antidiabetics, antihypertensives, and antioxidants available to treat diabetic nephropathy; most of patients continue to show progressive renal damage. It suggests that the key pathogenic mechanism involved in the induction and progression of diabetic nephropathy is still remaining active and unmodified by the present therapies. The purpose of this review is to bring together the current information concerning the signalling systems involved in the pathogenesis of diabetic nephropathy.
International Journal of Basic & Clinical Pharmacology, 2025
Diabetic nephropathy is the chronic loss of kidney function occurring due to diabetes mellitus. Due to increased sugar levels, there is disfunctioning of glomeruli, loss of protein in urine, and decrease in the levels of serum albumin that mainly leads to edema. The progression of renal disfunctioning starts when glomerular filtration rate is greater than 90ml/min. A large body of evidence indicates that oxidative stress is the main attributor involved in the progression of macro-vascular complications of diabetes. (ROS), NAD(P)H oxidase, advanced glycation end products (AGE), polyol pathway, uncoupled nitric oxide synthase (NOS), mitochondrial respiratory chain via oxidative phosphorylation, protein kinase C, mitogen-activated protein kinases, cytokines and transcription factors eventually cause increased expression of extracellular matrix (EC) genes with progression to fibrosis and end stage renal disease. Apart from these well-established pathways, major markers in the kidney disease which could work as potential targets has been explored like MCP-1, BMP-7, p38 MAPK, MiR-130b, HSP-27, AKT which further needs more research as they have shown promising results in their early level of studies. The present review aims to investigate the molecular targets involved in diabetic nephropathy, and to comprehend the intricate signalling pathways, such as JAK/STAT, BMP-7–Smad1/5/8 pathway, RhoA/ROCK, caspases, to which the aforementioned markers have either an independent or dependent relationship. If these signalling pathways are properly studied, these markers may aid in the treatment of the disease and its associated secondary effects such as nephropathy.
2018
Diabetic nephropathy (DN) is a major micro-vascular complication in diabetes mellitus (DM). One third of type 1 DM and 1/6 of type 2 DM develop DN account for more than 30% of total end stage renal disorders (ESRD), the main cause of renal replacement therapy. It is characterized by mesangial expansion, glomerulosclerosis and increased intracellular matrix accumulation. Injury of podocytes and reduced cellular density are considered to be root of the disease. Molecular mechanisms that leads diabetic patients toward nephropathy is hyperglycemia induced production of reactive oxygen species (ROS), advanced glycation end products (AGEs), activation of polyol pathway, increased expression of TGF-β, angiotensin II and aldosterone induced oxidative injury. DN can be prevented by controlling the glycemic levels, blood pressure, body weight and consumption of low protein diets along with high potassium supplementation. Therapeutic strategies including intensive glycemic control, blockage of...
Progression of diabetic nephropathy
American Journal of Kidney Diseases, 2003
Diabetic nephropathy, a kidney disease caused by diabetes, is the most devastating and money-consuming complication in patients with diabetes throughout the world. The cardinal lesion of diabetic nephropathy resides in renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is responsible for the development and progression of diabetic nephropathy through metabolic derangements, including increased oxidative stress, renal polyol formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases (MAPKs), and accumulation of advanced glycation end products, as well as such hemodynamic factors as systemic hypertension and increased intraglomerular pressure. We examined whether inhibition of the PKC-MAPK pathway could inhibit functional and pathological abnormalities in glomeruli from diabetic animal models and cultured mesangial cells exposed to high glucose condition and/or mechanical stretch. Direct inhibition of PKC by PKC beta inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model of type 2 diabetes. We also found that inhibition of MAPK by PD98059, an inhibitor of MAPK, or mitogen-activated extracellular regulated protein kinase kinase prevented enhancement of activated protein-1 (AP-1) DNA binding activity and fibronectin expression in cultured mesangial cells exposed to mechanical stretch in an in vivo model of glomerular hypertension. These findings highlight the important role of PKC-MAPK pathway activation in mediating the development and progression of diabetic nephropathy.
Glucose and Blood Pressure-Dependent Pathways–The Progression of Diabetic Kidney Disease
International Journal of Molecular Sciences, 2020
The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.
Diabetes, 2003
Oxidative stress is implicated to play an important role in the development of diabetic vascular complications, including diabetic nephropathy. It is unclear whether oxidative stress is primarily enhanced in the diabetic glomeruli or whether it is merely a consequence of diabetes-induced glomerular injury. To address this issue, we examined diabetic glomeruli to determine whether oxidative stress is enhanced, as well as examined the role of protein kinase C (PKC)-beta activation in modulating NADPH oxidase activity. Urinary 8-hydroxydeoxyguanosine excretion and its intense immune-reactive staining in the glomeruli were markedly higher in diabetic than in control rats, and these alterations were ameliorated by a treatment with a selective PKC-beta inhibitor, ruboxistaurin (RBX; LY333531) mesylate, without affecting glycemia. NADPH oxidase activity, which was significantly enhanced in diabetic glomeruli and the source of reactive oxygen species (ROS) generation, was also improved by RBX treatment by preventing the membranous translocation of p47phox and p67phox from cytoplasmic fraction without affecting their protein levels. Adenoviral-mediated PKC-beta(2) overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells. We now demonstrate that oxidative stress is primarily enhanced in the diabetic glomeruli due to a PKC-beta-dependent activation of NADPH oxidase resulting in ROS generation.
Activation of renal signaling pathways in db/db mice with type 2 diabetes
Kidney International, 2001
Activation of renal signaling pathways in db/db mice with type growth factors, it is now evident that metabolic and phys-2 diabetes. ical factors such as hyperglycemia, osmolality, and stretch Background. Altered regulation of signaling pathways may also activate signaling pathways and elicit phenotypic contribute to the pathogenesis of renal disease. We examined changes in target tissues [1, 2]. Elevation of ambient renal cortical signaling pathways in type 2 diabetes. plasma glucose concentration is a primary pathogenetic Methods. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in factor in microvascular complications in both type 1 and the early phase of diabetic nephropathy associated with renal type 2 diabetes mellitus [3, 4]. The primacy of glucose matrix expansion and albuminuria. in diabetic complications has led to studies on regulation Results. Tyrosine phosphorylation of renal cortical proteins of signaling by glucose in several tissues. In the kidney, was increased in diabetic mice. Renal cortical activities of phosa major site of microvascular complications, glomerular phatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates, Akt (PKB), and ERK1/2-type mitogenactivity of protein kinase C (PKC) is increased in rats activated protein (MAP) kinase activities were significantly with streptozotocin-induced type 1 diabetes [5, 6]. Increaugmented sixfold (P Ͻ 0.01), twofold (P Ͻ 0.0003), and sevment in composite PKC activity involved activation of enfold (P Ͻ 0.001), respectively, in diabetic mice compared PKC [7], although an increase in activities of other with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation, as PI 3-kinase isoenzymes of PKC is also reported [8]. Among other activity associated with  chain of the insulin receptor was signaling molecules, the activities of Erk1/2-type mitoincreased nearly fourfold (P Ͻ 0.0235). Additionally, the kinase gen-activated protein (MAP) kinase (ERK) and its upactivity of the immunoprecipitated insulin receptor  chain stream regulator, MEK, are augmented in glomeruli of was augmented in the diabetic renal cortex, and tyrosine phosrat with type 1 diabetes [9]. Increased ERK activity apphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunopears to be partly due to reduction in the activity of precipitates and Akt also were increased threefold (P Ͻ 0.05) MAPK phosphatase-1 (MKP-1), and in vitro studies sugand twofold (P Ͻ 0.0002), respectively. However, there was gest that MAPK activation is PKC dependent [9, 10]. no change in the hepatic insulin receptor-associated PI 3-kinase Increased PKC activity in renal tissue has functional activity. Additionally, the hepatic ERK1/2-type MAP kinase implications as LY333531, a PKC-specific inhibitor, reactivity was inhibited by nearly 50% (P Ͻ 0.01). Conclusions. These studies demonstrate that a variety of verses the increase in both glomerular filtration rate and receptor signaling pathways are activated in the renal cortex microalbuminuria in rats with type 1 diabetes [6]. of mice with type 2 diabetes, and suggest a role for augmented Similar to type 1 diabetes, activation of glomerular insulin receptor activity in nephropathy of type 2 diabetes. PKC occurs in mice with type 2 diabetes [11]. However, the administration of LY333531 resulted in partial ame-Altered regulation of signaling pathways is gaining lioration of functional abnormalities such as albuminincreasing recognition as an important mechanism in the uria, despite the complete reversal of glomerular PKC pathogenesis of renal disease. In addition to soluble activation [11]. It is likely that in addition to PKC, other signaling pathways are also involved in pathogenesis of renal disease in type 2 diabetes. Notwithstanding the