title: Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism.
abstract: 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-beta1 production. TGF-beta1 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.
authors.affiliation: Cardiovascular Division, King's College London, Guy's Hospital, London SE1 9RT, UK. luigi.gnudi@kcl.ac.uk
authors.forename: Luigi
authors.initials: L
authors.lastname: Gnudi
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Viberti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology*; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: D001786:Blood Glucose