Experimental membranous nephropathy redux

Abstract

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.

Complement-mediated Activation of Calcium-independent Phospholipase A2γ

“…Thus, both cPLA 2 ␣ and iPLA 2 ␥ can contribute to complement-dependent release of AA. Previous studies in GECs demonstrated that complement induced an increase in cPLA 2 ␣ catalytic activity, in association with Ser-505 phosphorylation, although this phosphorylation was not essential for cPLA 2 ␣ activation (12,13). In addition, glomerular cPLA 2 ␣ was phosphorylated in vivo in passive Heymann nephritis (51).…”

“…C5b-9 can activate MAPK pathways in GECs (12,13). In GECs overexpressing GFP-iPLA 2 ␥ WT, the complement-induced release of PGE 2 was blocked by two distinct chemical inhibitors of both the ERK and p38 pathways but not JNK (Fig.…”

“…In previous studies it was demonstrated that C5b-9 can activate cPLA 2 ␣ to augment production of [ 3 H]AA and prostanoids (12,13 (16,52). Thus, both cPLA 2 ␣ and iPLA 2 ␥ can contribute to complement-dependent release of AA.…”

“…contribute to changes in GEC lipid structure and function, actin cytoskeleton reorganization, and displacement of filtration slit diaphragm proteins, ultimately resulting in proteinuria (12,13,16). Recently, we demonstrated that C5b-9 stimulated a Ca 2ϩ -independent PLA 2 activity in GECs, and complement-induced release of [ 3 H]AA and prostaglandin E 2 (PGE 2 ) was amplified in GECs that overexpress iPLA 2 ␥ (13, 16).…”

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

“…The resulting immune complexes activate the complement system, leading to the assembly of the C5b-9 membrane attack complex (6). Nucleated cells require multiple C5b-9 lesions for lysis, but at lower doses, C5b-9 induces sublethal (sublytic) injury and various metabolic effects (7). A previous study reported complement-dependent disruption of the actin microfilaments in cultured GEC (8), which may explain the altered cell-matrix interaction and impaired permselectivity that occur in podocytes in membranous nephropathy (8).…”