[Molecular bases of diabetic nephropathy].
The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.
Lagranha
Claudia J
CJ
Laboratório de Hipertensão Experimental, Unidade de Hipertensão, Instituto do Coração, HC-FMUSP, São Paulo.
Fiorino
Patricia
P
Casarini
Dulce Elena
DE
Schaan
Beatriz D'Agord
BD
Irigoyen
Maria Claudia
MC
D000804:Angiotensin II / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D012598:Sclerosis / Q000378:metabolism / Q000503:physiopathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000378:metabolism
D045462:Endothelium-Dependent Relaxing Factors; D051272:Glucose Transporter Type 1; D017127:Glycation End Products, Advanced; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide