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Mechanical Forces in Diabetic Kidney Disease: A Trigger for Impaired Glucose Metabolism

Cardiovascular Division, King's College London School of Medicine, Guy's Hospital, London, United Kingdom

Correspondence: Dr. Luigi Gnudi, Department of Diabetes, Endocrinology and Internal Medicine, 5th Floor Thomas Guy House, Guy's Hospital, St. Thomas Street, London SE1 9RT, UK. Phone: +44-20-7188-1939; Fax: +44-20-7188-0146; E-mail: luigi.gnudi{at}kcl.ac.uk

Nephropathy is one of the major microvascular complications of diabetes, and both hemodynamic and metabolic stimuli participate in its development and progression toward ESRD. There is now a greater understanding of the molecular pathways that are activated by high glomerular capillary pressure and hyperglycemia and how they interplay to produce kidney pathology. The observation that overexpression of glucose transporter 1 (GLUT-1) in mesangial cells could induce a "diabetic cellular phenotype" has led to the postulation that the expression of GLUT-1 could be upregulated in glomeruli that are exposed to high pressure. This review suggests a mechanism by which mechanical forces may aggravate a metabolic insult by stimulating excessive cellular glucose uptake. Proposed is the existence of a self-maintaining cycle whereby a hemodynamic stimulus on glomerular cells induces GLUT-1 overexpression followed by greater glucose uptake and activation of intracellular glucose metabolic pathways, resulting in excess TGF-1 production. TGF-1 in turn, maintains overexpression of GLUT-1, perpetuating a signaling sequence that has, as its ultimate effect, increased extracellular matrix synthesis. This mechanical and metabolic coupling suggests a novel pathophysiologic mechanism of injury in the kidney in diabetes and possibly other glomerular diseases.

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				Y. Qian, E. Feldman, S. Pennathur, M. Kretzler, and F. C. Brosius III From Fibrosis to Sclerosis: Mechanisms of Glomerulosclerosis in Diabetic Nephropathy Diabetes, June 1, 2008; 57(6): 1439 - 1445. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673