ABSTRACT
Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3ß phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.
Subject(s)
Capillaries/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Kidney Glomerulus/blood supply , Nogo Proteins/metabolism , Angiopoietin-1/metabolism , Angiopoietin-2/metabolism , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/genetics , Diabetic Nephropathies/blood , Diabetic Nephropathies/genetics , Humans , Kidney Glomerulus/metabolism , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Nitric Oxide Synthase Type III/metabolism , Nogo Proteins/blood , Nogo Proteins/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Diabetic nephropathy is the commonest cause of end-stage renal disease and affects between 30 and 45% of patients with diabetes mellitus. There is no cure for diabetic nephropathy and the current management of this condition includes glycaemic control, blockade of the renin-angiotensin aldosterone system and lifestyle changes. However, many patients eventually progress to end-stage renal disease. The exact pathogenesis of diabetic nephropathy is still being researched, and recent advances have led to the development of several novel potential therapeutic targets. There are a number of different experimental therapies that are currently being assessed. Generally, these can be separated into drugs targeting vasculature/haemodynamic effects, drugs targeting inflammation and drugs targeting oxidative stress. Drugs targeting the vasculature include Tie-2 activators, -sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. Anti-inflammatory therapies include inflammatory cytokines inhibitors, pentoxifylline, as well as anti-transforming growth factor α/-epiregulin therapies. Finally, anti-oxidative stress therapies include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors and allopurinol. Many new trials are providing promising results and it is likely that some of these therapies will be available for clinical use within the next decade. This article will seek to outline the main advancements in each of these experimental therapies for diabetic nephropathy. Results: Abnormal vascular remodelling, inflammation and oxidative stress seem to be the 3 main sources from which future new drugs for diabetic kidney disease will originate.
