Immunological and non-immunological mechanisms of proteinuria.
Proteinuria as a general symptom of a broad range of different diseases can result from gene mutations of molecules building up the glomerular sieve, from immune-mediated, haemodynamic or metabolic disturbances of the glomerular filter. This filter is not a static barrier but consists of a highly dynamic interacting podocyte foot process to foot process to glomerular basement membrane complex. Its function is to prevent leakage of macromolecules and blood cells into the urine. Molecules like nephrin and podocin are directly involved in the formation of the slit diaphragm located at the end of the foot processes. Other molecules, i.e. CD2AP, play a role in organizing the correct position of the podocytes and its foot processes via controlling intra-cellular actin filaments. Gene mutations coding for these molecules directly cause proteinuric diseases. Autoantibodies or circulating immune complexes can destroy this fragile network of cells and the basement membrane via accumulation of inflammatory cells, cytokines and generation of oxygen radicals. Hemodynamic and metabolic changes as seen in diabetic nephropathy are associated with increased TGF-ss expression and extra-cellular matrix expansion in the mesangium and a decrease of podocyte numbers. Thus, proteinuria is the result of a disturbance of the highly fragile network of cells and the basement membrane on the micro-anatomical and molecular level.
Braun
N
N
HELIOS Kliniken, Department of Nephrology and Dialysis Faculty of Medicine, University of Rostock, Rostock, Germany. norbert.braun@helios-kliniken.de
Gröne
H J
HJ
Schena
F P
FP
D050533:Glomerular Basement Membrane / Q000033:anatomy & histology / Q000502:physiology; D015433:Glomerulonephritis, Membranous / Q000150:complications; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications; D006801:Humans; D008181:Lupus Nephritis / Q000150:complications; D050199:Podocytes / Q000502:physiology; D011507:Proteinuria / Q000209:etiology / Q000276:immunology*