Differential inflammatory stages in the eyes and kidneys of aged complement factor H-deficient mice

Abstract

Purpose: Complement factor H dysfunction has been implicated in membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). To investigate the role of factor H in kidney and ocular diseases, aged complement factor H-deficient mice (CFH-/-) were evaluated for inflammatory proteins and gene expression in kidney and eye tissue.

Methods: CFH+/+, CFH+/-, and CFH-/- mice were generated from Het x Het breeding and were aged up to 18 months. Kidney pathology was assessed by urine albumin ELISA and histology. Complement activity was measured by monitoring complement breakdown products and C3 deposition in kidney sections. Visual function was assessed using electroretinography (ERG). Renal and ocular inflammation was monitored by a myeloperoxidase assay (MPO), multiplex cytokine analysis, and microarray analysis of inflammatory gene expression.

Results: 12-18 month old CFH-/- mice exhibited low levels of inflammation, mild albuminuria (~50 ug/ml) and 80% elevated kidney MPO as the result of continuous uncontrolled complement activation and glomerular C3 deposition. Compared to CFH+/+ controls, levels of several inflammatory mediators (ICAM1, MIP1a, MMP9, and VCAM1) were also elevated in the kidneys of CFH-/- mice, whereas IFNγ and IL17 were moderately increased in their eyes. Evaluation of ocular pathology (fundus photography and histology) revealed no observable changes between 12-18 month old CFH-/- and CFH+/+ mice. No clear differences in ERG were detected between the genotypes. The expression of AMD-associated genes involved in the complement system and immune responses (C3, FB, CFI, MMP9, CX3CR1, CXCL1/2) were elevated in aged CFH-/- mouse kidneys, but down-regulated in ocular tissue.

Conclusions: Chronic over-activation of the alternative complement pathway caused mild inflammation in the kidneys of aged CFH-/- mice. However, the inflammatory readouts in the eye were few and distinct from the kidney. Thus, the deletion of CFH in aged mice leads to kidney damage that precedes ocular pathology. This is consistent with the disease progression in MPGN patients where renal impairment is detected prior to the onset of drusen.

Keywords: 412 age-related macular degeneration • 557 inflammation • 490 cytokines/chemokines