Cellular response to injury in membranous nephropathy.
The pathogenesis of membranous nephropathy (MN) involves in situ formation of subepithelial immune deposits that produce glomerular injury by damaging and/or activating podocytes through complement-dependent processes. C5b-9 formation and insertion into podocyte cell membranes causes glomerular injury in MN. C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines including TGF-beta. C5b-9 also causes alterations of the cytoskeleton that lead to abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into Bowman's space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria. Complement components in proteinuric urine also induce tubular epithelial cell injury and mediate progressive interstitial disease in MN. Measurements of urinary C5b-9 or podocyte excretion in the urine may be useful in the diagnosis of MN and as measures of disease activity and response to therapy. Recent studies of cell-cycle proteins and DNA damage in podocytes have clarified why podocytes fail to proliferate in response to C5b-9-mediated injury and podocyte loss in MN, resulting in the development of glomerular sclerosis and renal failure. Improved understanding of the role of complement in the pathogenesis of MN and of the cellular response to C5b-9 attack creates several new opportunities for therapeutic intervention that may benefit patients with MN in the future.
Nangaku
Masaomi
M
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
Shankland
Stuart J
SJ
Couser
William G
WG
D015938:Complement Membrane Attack Complex / Q000276:immunology*; D015433:Glomerulonephritis, Membranous / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology*
D015938:Complement Membrane Attack Complex