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.