title: Complement regulation in renal disease models.
abstract: Activation of the complement system is tightly regulated by plasma and cell-associated complement regulatory proteins (CRPs), such as factor H (fH), decay-accelerating factor, and membrane cofactor protein. Animal models of disease have provided considerable insights into the important roles for CRPs in the kidney. Mice deficient in fH have excessive fluid phase C3 activation and inactivation, leading to deposition of inactivated C3b in glomerular capillary walls (GCW), comparable with dense deposit disease. In contrast, when fH lacks C-terminal surface targeting regions, local activation on the GCW leads to a disease reminiscent of thrombotic microangiopathy. The uniquely rodent protein, CR1-related y (Crry), has features analogous to human membrane cofactor protein. Defective Crry leads to unrestricted alternative pathway activation in the tubulointerstitium, resulting in pathologic features ranging from thrombotic microangiopathy (TMA), acute kidney injury, and tubulointerstitium nephritis. In the presence of initiators of the classic or lectin pathways, commonly in the form of immune complexes in human glomerular diseases, complement regulation is stressed, with the potential for recruitment of the spontaneously active alternative pathway. The threshold for this activation is set by CRPs; pathology is more likely when complement regulation is defective. Within the endocapillary region of the GCW, fH is key, while decay-accelerating factor and Crry are protective on mesangial cells and podocytes. Arguably, acquired alterations in these CRPs is a more common event, extending from pathologic states of cellular injury or production of inhibitory antibodies, to physiological fine tuning of the adaptive immune response.
authors.affiliation: Section of Nephrology, University of Chicago, Chicago, IL.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Naik
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D017242:Complement Factor H / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D015433:Glomerulonephritis, Membranous / Q000276:immunology*; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology*; D051379:Mice; D057049:Thrombotic Microangiopathies / Q000276:immunology*
chemical_list: D017242:Complement Factor H; D003165:Complement System Proteins
keywords: Complement; factor H; glomerulonephritis; membranous nephropathy; thrombotic microangiopathy