Mouse Podocyte Complement Factor H

Abstract

Complement factor H (Cfh) is a key plasma protein in humans and animals that serves to limit alternative pathway complement activation in plasma, as well as in local sites such as capillaries of the glomerulus and eye. It was shown that rodent Cfh on platelets is the functional analogue to human erythrocyte complement receptor 1 with a role that is distinct from plasma Cfh and that Cfh is also on cultured rodent podocytes. For investigation of the role of Cfh in the kidney, renal transplants were performed between wild-type (WT) and Cfh(-/-) C57BL/6 mice. For these studies, bilateral native nephrectomies were done so that renal function was dependent solely on the transplanted kidney. Chronic serum sickness was induced by active immunization with apoferritin. Diffuse proliferative glomerulonephritis (GN) occurred in WT kidneys that were transplanted into Cfh(-/-) recipients (n = 8) but not into WT recipients (n = 14), consistent with the importance of plasma Cfh to dictate outcome in this disease model. Relative to the WT recipients of WT kidneys, WT mice with Cfh(-/-) kidneys (n = 12) developed glomerular disease features, including increased albuminuria (82.8 +/- 7.0 versus 45.1 +/- 3.6 microg/mg creatinine; P < 0.001) and blood urea nitrogen levels (54.4 +/- 6.1 versus 44.2 +/- 3.7 mg/dl; P < 0.01). In addition, they had substantial glomerular capillary wall deposits of IgG and C3, which by electron microscopy were present in subendothelial and subepithelial immune deposits, whereas WT kidneys in WT hosts had almost exclusive mesangial deposits. The IgG deposits in Cfh(-/-) kidneys were adjacent to Cfh-deficient podocytes, whereas WT kidneys in a Cfh(-/-) host had podocyte-associated Cfh with absent IgG deposits. These data suggest that locally produced podocyte Cfh is important to process immune complexes in the subepithelial space, where it also limits complement activation. Just as in platelets, rodent podocytes seem to use Cfh as the functional surrogate for human complement receptor 1.