Molecular mechanisms of proteinuria in diabetes.
The epidemic of Type 2 diabetes, and the parallel rising incidence of end-stage renal disease, is progressively increasing worldwide. Kidney disease is one of the major chronic microvascular complications of diabetes, and both metabolic and haemodynamic perturbations participate in its development and progression towards end-stage renal disease. Hypertension and poor metabolic control seem to interact in causing the relentless decline in renal function seen in diabetic patients. Both high circulating glucose levels and increased glomerular capillary pressure act in conjunction in stimulating the different cellular pathways leading to kidney disease. It has been suggested that mechanical forces at the glomerular level may aggravate the metabolic insult by stimulating excessive cellular glucose uptake by up-regulating the facilitative GLUT-1 (glucose transporter-1). We propose the existence of a self-maintaining cellular mechanism whereby a haemodynamic stimulus on glomerular cells induces the up-regulation of GLUT-1, an event followed by greater glucose uptake and activation of intracellular metabolic pathways, resulting in excess TGF-beta1 (transforming growth factor-beta1) production. TGF-beta1, one of the major prosclerotic cytokines in diabetic kidney disease, maintains the up-regulation of GLUT-1, perpetuating a series of cellular events that result, as their ultimate effect, in increased extracellular matrix synthesis and altered permeability of the glomerular filtration barrier. Mechanical and metabolic coupling could represent an important mechanism of injury in the diabetic kidney.
Gnudi
Luigi
L
Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, Cardiovascular Division, King's College London School of Medicine, 3rd Floor Southwark Wing, Guy's Hospital, London SE1 9RT, UK. luigi.gnudi@kcl.ac.uk
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D001786:Blood Glucose; D027342:Excitatory Amino Acid Transporter 2; D053773:Transforming Growth Factor beta1