title: Complement-mediated cellular injury.
abstract: Complement activation and recruitment of inflammatory leukocytes is an important defense mechanism against bacterial infection. However, complement also can mediate cellular injury and contribute to the pathogenesis of various diseases. With the appreciation that the C5b-9 membrane attack complex can injure cells in the absence of leukocytes, a role for the terminal complement pathway in inducing cell injury and kidney disease was shown in several experimental models, including the rat passive Heymann nephritis model of human membranous nephropathy. In podocytes, sublytic C5b-9 activates a variety of downstream pathways including protein kinases, lipid metabolism, reactive oxygen species, growth factors/gene transcription, endoplasmic reticulum stress, and the ubiquitin-proteasome system, and it impacts the integrity of the cytoskeleton and slit diaphragm proteins. C5b-9 also injures other kidney cells, including mesangial, glomerular endothelial, and tubular epithelial cells, and it contributes to the pathogenesis of mesangial-proliferative glomerulonephritis, thrombotic microangiopathy, and acute kidney injury. Conversely, certain C5b-9 signals limit complement-induced injury, or promote recovery of cells. In addition to C5b-9, complement cleavage products, such as C5a and C1q, can injure kidney cells. Thus, the complement system contributes to various kidney pathologies by causing cellular damage in both an inflammation-dependent and inflammation-independent manner.
authors.affiliation: Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. Electronic address: tomoko.takano@mcgill.ca.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.forename: Hanan
authors.initials: H
authors.lastname: Elimam
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology*; D003167:Complement Activation / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D010740:Phospholipases / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats
chemical_list: D015938:Complement Membrane Attack Complex; D011494:Protein Kinases; D010740:Phospholipases
keywords: C5b-9 membrane attack complex; cytoskeleton; glomerulonephritis; phospholipases; protein kinases