Membranous nephropathy.
The understanding of cellular and molecular mechanisms involved in the pathogenesis of membranous nephropathy (MN) has come from studies carried out in the Heymann nephritis model of MN in the rat, which closely resembles the clinical and pathologic features of the human disease. MN involves the in situ formation of subepithelial immune deposits as a result of circulating antibodies binding to podocyte antigens. Complement activation leads to assembly of C5b-9 on podocyte plasma membranes, and results in sublethal podocyte injury and proteinuria. The podocyte responds to sublethal C5b-9 attack by activating protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress pathways, proteinases, etc. These signals impact on cell metabolic pathways, the structure/function of lipids and key proteins in the cytoskeleton and slit diaphragm, and on the turnover of extracellular matrix components. Some effects of C5b-9, including dissolution of the actin cytoskeleton, loss of nephrin expression, reduction in F-actin-bound nephrin and loss of slit diaphragm integrity, affect podocytes adversely. Other effects of complement, such as endoplasmic reticulum stress, may limit injury or promote recovery. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, including the presence of autoantibodies directed to podocyte antigens in human MN. Increased understanding of nephritogenic antigens, complement activation, and the cellular signaling pathways and targets of C5b-9 will facilitate the design of new approaches to therapy of this important glomerular disease.
Department of Medicine, McGill University Health Centre, McGill University, Montreal, Que., Canada.
Andrey V
AV
Cybulsky
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D003167:Complement Activation / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000502:physiology; D004195:Disease Models, Animal; D015433:Glomerulonephritis, Membranous / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D050199:Podocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
D001323:Autoantibodies; D015938:Complement Membrane Attack Complex