Mediation of immune glomerular injury

Abstract

Although glomerular disease remains the most common cause of end-stage renal disease worldwide, major advances have been made recently in understanding the cellular and molecular mechanisms which mediate these disorders. Nephrotic syndrome in non inflammatory lesions such as minimal-change/focal sclerosis and MN results from disorders of the GEC which can be simulated in animal models by antibodies to various GEC membrane epitopes. Clarification of how these antibodies effect the GEC to induce a loss of glomerular barrier function should substantially improve understanding of the pathogenesis of minimal change/focal sclerosis. In MN, proteinuria is mediated primarily by C5b-9 through similar mechanisms that also involve the GEC as a target. Inflammatory glomerular lesions are induced by circulating inflammatory cells or proliferating resident glomerular cells. Understanding of how these cells induce tissue injury has also evolved considerably over the past decade. Neutrophil-induced disease involves leukocyte adhesion molecules in regulating neutrophil localization; proteases, oxidants, and myeloperoxidase in mediating injury and platelets in augmenting these processes. The activated mesangial cell exhibits altered phenotype and proliferation with release of oxidants and proteases. Mesangial cell proliferation may be initiated by basic fibroblast growth factor and is maintained by an autocrine mechanism involving PDGF. TGF-beta is important in the subsequent development of sclerosis. As understanding of these areas evolves, numerous new therapeutic strategies can now be devised, including agents which block or inhibit complement effects, oxidants, proteases, growth factors, and other cytokines. Appreciation of the role of several natural inhibitors of these mechanisms may also allow therapeutic manipulations that upregulate regulatory proteins, with a consequent therapeutic benefit.(ABSTRACT TRUNCATED AT 250 WORDS)