Diabetic Nephropathy - Pathology
Metabolic and Haemodynamic factors -
updated: 15 March 2008
Diabetic nephropathy: where hemodynamics meets metabolism
Exp Clin Endocrinol Diabetes. 2007 Feb;115(2):69-84
Forbes JM, Fukami K, Cooper ME.
Diabetic nephropathy (DN), the most common cause of end stage renal disease in developed nations, is thought to result from interactions between metabolic and haemodynamic factors. Specific metabolically driven, glucose dependent pathways are activated within diabetic renal tissues. These pathways induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). Haemodynamic factors are also implicated in the pathogenesis of DN and include elevations of systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin aldosterone system (RAAS), endothelin and urotensin. These altered hemodynamics act independently and in concert with metabolic pathways, to activate intracellular second messengers such as protein kinase C (PKC) and MAP kinase (MAPK), nuclear transcription factors such as nuclear factor-kappaB (NF-kappaB) and various growth factors such as the prosclerotic cytokines, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the angiogenic, permeability enhancing growth factor, vascular endothelial growth factor, VEGF. Ultimately these molecular mechanisms lead to increased renal albumin permeability, and extracellular matrix accumulation, which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis.In the past, the treatment of diabetic nephropathy has focused on control of hyperglycemia and the interruption of the RAAS with certain anti-hypertensive agents. Newer novel targets, some of which are linked to glucose dependent pathways, appear to be a major focus of new therapies directed against the development and progression of renal damage as a result of diabetes. It is likely that resolution of diabetic nephropathy will require synergistic therapies to target multiple mediators of this disease.
Publication Types:
Online - Abstract
Molecular mechanisms of diabetic nephropathy and its therapeutic intervention
Curr Drug Targets. 2007 Aug;8(8):952-9
Yamagishi S, Fukami K, Ueda S, Okuda S.
Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large landmark clinical studies have shown that intensive glucose control reduces the risk of the development and progression of diabetic nephropathy, and the blockade renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. However, diabetic nephropathy remains the leading cause of end-stage renal failure in developed countries. Therefore, to develop novel therapeutic strategies that specifically target diabetic nephropathy may be helpful for most patients with diabetes. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), and activation of the RAS and protein kinase C (PKC), elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. This article summarizes the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions that may prevent this devastating disorder even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.
Publication Types:
Online - Abstract
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