New approaches for treatment of diabetic nephropathy: the endothelium as a target for drug discovery (original) (raw)

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.

Novel avenues for treating diabetic nephropathy: new investigational drugs

Expert opinion on investigational drugs, 2017

At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed. Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD. Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further s...

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.

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.

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.

New modalities for treatment of diabetic nephropathy: a mini review

International journal of epidemiologic research, 2015

Background and aims: Diabetic nephropathy (DN) is the most common cause of end-stage renal failure which could increase the risk of cardiovascular disease and morbidity and mortality in patients. The aim of this study was to investigate new modalities for treatment of diabetic nephropathy. Methods:This study was a mini-review research to investigate drugs that are used for DN treatment. Results: Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blocker (ARB) are the bases of DN treatment during recent decades. Due to some of adverse reactions of these drugs like hyperkalemia and chronic cough, other drugs such as non dihydropridin Ca channel blockers, uric acid lowering drugs, renin antagonists, lipid lowering agents, oral hypoglycemic agents such as Thiazolidinediones, Vitamin D and selective endothelin receptor antagonists have been used in some studies for decreasing proteinuria and slowing progression of DN. The results of these studies are different and ...

Therapeutic Modalities in Diabetic Nephropathy: <i>Future Approaches</i&gt

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.