Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals

Abstract

Factor H is the major regulatory protein of the alternative pathway of complement activation. Abnormalities in factor H have been associated with renal disease, namely glomerulonephritis with C3 deposition including membranoproliferative glomerulonephritis (MPGN) and the atypical haemolytic uraemic syndrome (aHUS). Furthermore, a common factor H polymorphism has been identified as a risk factor for the development of age-related macular degeneration. These associations suggest that alternative pathway dysregulation is a common feature in the pathogenesis of these conditions. However, with respect to factor H-associated renal disease, it is now clear that distinct molecular defects in the protein underlie the pathogenesis of glomerulonephritis and HUS. In this paper we review the associations between human factor H dysfunction and renal disease and explore how observations in both spontaneous and engineered animal models of factor H dysfunction have contributed to our understanding of the pathogenesis of factor H-related renal disease.

Fig. 1

The spectrum of renal pathology associated with alternative pathway dysregulation. Factor H dysfunction is associated with haemolytic uraemic syndrome and glomerulonephritis with deposition of C3. The pathological manifestations of glomerulonephritis with deposition of C3 are heterogeneous and can be encompassed by the term C3 glomerulopathy. Numbers in parentheses refer to references.

Fig. 2

Electron micrographs of glomeruli from 12-month-old (a) C5-deficient mice, (b) factor H-deficient mice and (c) mice with combined deficiency of H and C5. The ultrastructural appearances of the glomeruli in the C5-deficient mice are normal. In contrast, in both the factor H-deficient and combined factor H and C5-deficient animals, subendothelial electron-dense glomerular basement membrane deposits are present (arrows indicate examples).

Fig. 3

Electron micrographs of glomeruli from 8-month-old (a) factor I-deficient and (b) mice with combined deficient of H and I. The ultrastructural appearances of the glomerular basement membrane are normal in both cases. In contrast, in both groups of mice the glomeruli contained mesangial electron-dense material corresponding to areas of nodular mesangial expansion seen by light microscopy (arrows indicate examples).