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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

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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 7

Glomerular C3 staining in renal transplant studies in Cfh–/– mice.

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Glomerular C3 staining in renal transplant studies in Cfh–/– mice.
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Kidneys from wild-type (A), Cfh–/–C3–/– (B), and Cfh–/– (D) mice were transplanted into Cfh–/– animals. Linear capillary wall C3 staining developed in both wild-type (A) and Cfh–/–C3–/– (B) kidneys transplanted into Cfh–/– animals. Transplantation of a wild-type kidney into a wild-type recipient did not result in abnormal glomerular C3 staining (C), and transplantation of a Cfh–/– kidney into a Cfh–/– recipient did not alter the abnormal glomerular C3 staining seen in unmanipulated Cfh–/– kidneys (D). Original magnification, ×40.

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