New approaches for treatment of diabetic nephropathy: the endothelium as a target for drug discovery (original) (raw)
Renal Endothelial Dysfunction in Diabetic Nephropathy
Cardiovascular & Hematological Disorders-Drug Targets, 2014
Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN). Due to the heterogeneity of endothelial cells (ECs), it is difficult to generalize about endothelial responses to diabetic stimuli. At present, there are limited techniques fordirectly measuring EC function in vivo, so diagnosis of endothelial disorders still largely depends on indirect assessment of mediators arising from EC injury. In the kidney microcirculation, both afferent and efferent arteries, arterioles and glomerular endothelial cells (GEnC) have all been implicated as targets of diabetic injury. Both hyperglycemia per se, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in EC dysfunction. Impaired eNOS activity can occur at numerous levels, including enzyme uncoupling, post-translational modifications, internalization and decreased expression. Reduced nitric oxide (NO) bioavailability exacerbates oxidative stress, further promoting endothelial dysfunction and injury. The injured ECs may then function as active signal transducers of metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interact with adjacent cells, which may activate a cascade of inflammatory and proliferative and profibrotic responses in progressive DN. Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.
Endothelial dysfunction as a potential contributor in diabetic nephropathy
Nature Reviews Nephrology, 2011
The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.
Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches
Journal of General Internal Medicine, 2011
Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.
Current Issues in Molecular Biology
Diabetes mellitus (DM) is a frequent medical problem, affecting more than 4% of the population in most countries. In the context of diabetes, the vascular endothelium can play a crucial pathophysiological role. If a healthy endothelium—which is a dynamic endocrine organ with autocrine and paracrine activity—regulates vascular tone and permeability and assures a proper balance between coagulation and fibrinolysis, and vasodilation and vasoconstriction, then, in contrast, a dysfunctional endothelium has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes. Hyperglycemia is indicated to be the major causative factor in the development of endothelial dysfunction. Furthermore, many shreds of evidence suggest that the progression of insulin resistance in type 2 diabetes is parallel to the advancement of endothelial dysfunction in atherosclerosis. To present the state-of-the-art data regarding endothelial dysfunction in diabetic micro...
Renal Disease in Diabetes Mellitus: Recent Studies and Potential Therapies
Journal of Diabetes & Metabolism, 2013
Diabetic kidney disease is the predominant cause of end stage kidney disease in North America, estimated to be 152 per million population in 2010. New guidelines published by KDIGO on Chronic Kidney Disease classification are discussed. In light of recent clinical trials, better insight has been gained on how improve management of diabetic patients to prevent renal disease and its progression, especially with regards to metabolic and blood pressure control. Unfortunately, studies of newer therapies such as endothelin 1 antagonists and bardoxolone methyl have been disappointing, but several other possible therapeutic agents are under investigation and may provide hope for patients with diabetes mellitus in the future.
The vascular endothelium in diabetes: a practical target fordrug treatment?
Expert Opinion on Therapeutic Targets, 2005
Vascular disease remains a major cause of morbidity and mortality in diabetes mellitus, in spite of recent improvements in outcome, some of which may be modulated by improved endothelial function. Therapeutic strategies aimed directly at preventing, or minimising the extent of, these sequelae are required as an adjunct to treatments directed at normalising the metabolic milieu. The microvasculature, and the endothelium in particular, are early contributors to vascular dysfunction, thus raising the question as to how best to specifically target the endothelium. However, the expansive nature of the microvasculature, the varying demands that tissues have in terms of blood flow, and the heterogeneity that exists amongst cell types in different sites raises potential problems as to the practicality of such an approach. Furthermore, temporal and genetic factors in the genesis of diabetic microvascular dysfunction may impact on therapeutic strategies. It is suggested that a systematic approach is required to understand the heterogeneity of the microvasculature, with particular emphasis on relating differences in gene and protein expression with functional properties. Such an approach may then provide the necessary information to allow exploitation of endothelial cell heterogeneity for unique targeted interventions, as well as providing the necessary rationale for pharmacological interventions (both prophylactic and corrective) aimed at the endothelium as a whole.
Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy
Journal of The American Society of Nephrology, 2007
The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.
Drug Therapy Targets for Diabetic Nephropathy: An Overview
International Journal of Pharmaceutical Sciences Review and Research
Diabetic nephropathy is a leading cause of chronic kidney disease and end stage renal disease and accounts for significant morbidity and mortality in diabetic patients. Hyperglycemia may lead to end stage renal damage through both metabolic and non metabolic pathways. The non-enzymatic glycation of proteins with irreversible formation and deposition of reactive advanced glycation end products (AGE) have been noted to play a major role in the pathogenesis of diabetic nephropathy. Further, diabetic nephropathy is associated with hyperactivity of sorbitol aldose reductase pathway, hyperactivity of hexosamine biosynthetic pathway, activation of protein kinase C and MAPK and overexpression of growth factors and cytokines i.e. transforming growth factor-β, vascular endothelial growth factor, platelet-derived growth factor and insulin-like growth factor. Moreover, high glucose concentration in diabetes has been noted to induce oxidative and nitrosative stress, activate intracellular RAAS and release endothelin-1 and prostaglandins to deteriorate the function of kidney. In addition, up-regulation of transforming growth factor-β (TGF-β) and consequent overproduction of extracellular matrix molecules have been implicated in the progression of diabetic nephropathy. The present review study the various drug targets and drug therapy in diabetic nephropathy.
Potential New Therapeutic Agents for Diabetic Kidney Disease
American Journal of Kidney Diseases, 2010
Diabetic nephropathy is the leading cause of end-stage renal disease, and both the incidence and prevalence of diabetic nephropathy continue to increase. Currently, various treatment regimens and combinations of therapies provide only partial renoprotection. It is obvious that new approaches are desperately needed to retard the progression of diabetic nephropathy. Recently, a number of new agents have been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of end-stage renal disease. These include inhibitors and breakers of advanced glycation end products, receptor antagonists for advanced glycation end products, protein kinase C inhibitors, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitors, glycosaminoglycans, endothelin receptor antagonists, antifibrotic agents, and growth factor inhibitors. This review addresses these promising new therapeutic agents for delaying the progression of diabetic kidney disease. Am J Kidney Dis 55:928-940.
Revisiting Experimental Models of Diabetic Nephropathy
International Journal of Molecular Sciences, 2020
Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to...
Therapeutic Modalities in Diabetic Nephropathy: <i>Future Approaches</i>
Open journal of nephrology, 2012
Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Several therapeutic interventions for the treatment of diabetic nephropathy have been developed and implemented over the past few decades with some degree of success. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are therefore urgently needed. Recently, several novel therapeutic strategies have been explored in treating DN patients including Islet cell transplant, Aldose reductase inhibitors, Sulodexide (GAC), Protein Kinase C (PKC) inhibitors, Connective tissue growth factor (CTGF) inhibitors, Transforming growth factor-beta (TGF-β) inhibitors and bardoxolone. The benefits and risks of these agents are still under investigation. This review aims to summarize the utility of these novel therapeutic approaches.
The British Journal of Diabetes & Vascular Disease, 2007
V ascular disease is the most important complication of both type 1 and type 2 diabetes, with both micro-and macrovascular disease underlying most of the death and disability observed in diabetic patients. Endothelial dysfunction is a cardinal feature of both types of diabetes, and is believed to be involved in the aetiology and pathophysiology of diabetic vasculopathy. Therefore, measures which improve endothelial dysfunction in diabetes are currently the subject of much interest and research. In this article, we review both drug and non-drug therapies for endothelial dysfunction, along with evidence of their effectiveness in diabetes. We suggest that those therapies for which good evidence of endothelial benefit exists should be more widely used in diabetic patients, and that the maximum benefit will be derived by using multiple such therapies in combination.
Brief overview on pathogenesis and treatment of diabetic nephropathy
Diabetic nephropathy is a serious condition affecting the patients worldwide suffering from diabetes mellitus. Diabetic nephropathy is the leading cause of Chronic Kidney Disease (CKD) in diabetic patients. About 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes are more predisposed to develop diabetic kidney disease. The current review focuses on the current statistical scenario of diabetic nephropathy, its causes and the current treatment which is available for the treatment of this serious condition.
Present and Future in the Treatment of Diabetic Kidney Disease
Journal of Diabetes Research, 2015
Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade.
Overview: Combating Diabetic Nephropathy
Journal of the American Society of Nephrology, 2003
Much has been said in the scientific and lay media about the growing epidemic of diabetes around the globe, but individuals and societies should never lose sight of the immeasurable human suffering and the enormous healthcare costs that this epidemic exacts. With the growing population of type 2 diabetes, the prevalence of diabetic nephropathy is on the rise, and there is an urgent need to define the pathophysiologic mechanisms for this devastating disorder. Genetic factors conspire with metabolic and hemodynamic insults to induce renal injury in susceptible individuals. In the current issue of the Journal of the American Society of Nephrology, four authoritative papers provide a balanced overview of the pathogenesis of the disease along with a comprehensive update on the clinical aspects and current management of diabetic nephropathy. Only by translating the new understanding of diabetic nephropathy into medical practice and implementing widespread clinical guidelines will we ever ensure that all at-risk patients receive the ideal care to stem the epidemic and stop nephropathy in its tracks.