Membranous nephropathy (MN) is a common cause of
nephrotic syndrome in adults. Active and passive
Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating
antibodies. Complement activation leads to assembly of
C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of
proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal
C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of
protein kinases,
phospholipases,
cyclooxygenases,
transcription factors,
growth factors,
NADPH oxidase,
stress proteins,
proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of
lipids and key
proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus
C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in
nephrin expression, reduction in
F-actin-bound
nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit
complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on
complement-regulatory
proteins, which act at early or late steps within the
complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.