Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice
Kirsten L. Rose, … , Marina Botto, Matthew C. Pickering
Kirsten L. Rose, … , Marina Botto, Matthew C. Pickering
Published January 17, 2008
Citation Information: J Clin Invest. 2008;118(2):608-618. https://doi.org/10.1172/JCI32525.
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Research Article Nephrology

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Abstract

The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I–mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency.

Authors

Kirsten L. Rose, Danielle Paixao-Cavalcante, Jennifer Fish, Anthony P. Manderson, Talat H. Malik, Anne E. Bygrave, Tao Lin, Steven H. Sacks, Mark J. Walport, H. Terence Cook, Marina Botto, Matthew C. Pickering

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Figure 5

Glomerular C3 staining and complement profile in mice with deficiency of both factor H and factor I.

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Glomerular C3 staining and complement profile in mice with deficiency of...
(A) Glomerular C3 staining in Cfi–/– mice with normal (Cfh+/+), heterozygous (Cfh+/–), and homozygous (Cfh–/–) factor H genotypes. A mesangial staining pattern was evident in the glomeruli of the Cfi–/– mice regardless of factor H genotype. Note the marked contrast in glomerular C3 staining pattern between the Cfi–/–Cfh–/– mice and that seen in mice with factor H deficiency alone (Figure 4B). Original magnification, ×40. Plasma C3 (B) and factor B (C) levels in Cfi–/– mice with heterozygous and homozygous factor H deficiency. Horizontal bars denote median values. (D) Western blot for C3 from Cfi–/– and Cfi–/–Cfh–/– mice under reducing conditions. On this high-exposure α-chain, fragments were only present in the Cfh–/– EDTA plasma (lane 4). The lower molecular weight of the α′-chain (lanes 2, 3, and 4) compared with the intact α-chain (lane 1) was also evident. Also shown are sera from Cfi–/– and Cfi–/–Cfh–/– mice before and after incubation with murine sera deficient in C3 (as a source of autologous factors I and H). Note that in both Cfi–/– and Cfi–/–Cfh–/– mice, complete cleavage of the α′-chain occurred with the concomitant appearance of the 43-kDa α′-chain fragment that was evident in unmanipulated EDTA plasma taken from a Cfh–/– animal (lane 4). (E) Under nonreducing conditions C3c was detectable in EDTA plasma from Cfh–/– and wild-type mice, but not from Cfi–/– mice. Note that EDTA plasma dilutions were 1/1000 for wild-type and Cfi–/– mice and 1/100 for Cfh–/– mice.