Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy

Area of Science:

• Nephrology
• Immunology
• Complement System Biology

Background:

• C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated renal diseases linked to dysregulation of the complement alternative pathway (AP).
• Complement factor H (FH) is a key negative regulator of the AP, and its abnormalities lead to uncontrolled C3 activation, increasing susceptibility to C3G and aHUS.
• Existing FH-deficient animal models do not fully replicate clinical observations of these diseases.

Purpose of the Study:

• To investigate the role of liver-derived FH in the pathogenesis of C3G and aHUS.
• To develop a more clinically relevant animal model for studying complement-mediated renal diseases.

Main Methods:

• Generation of mice with hepatocyte-specific FH deficiency.
• Analysis of plasma FH and C3 levels, C5 levels, and glomerular C3 deposition.
• Induction of thrombotic microangiopathy via accelerated serum nephrotoxic nephritis.

Main Results:

• Hepatocyte-specific FH deficiency led to reduced plasma FH and C3 levels but not C5 depletion or glomerular C3 accumulation, unlike complete FH deficiency.
• Subtotal FH deficiency resulted in mesangial C3 accumulation, characteristic of C3G.
• These mice developed severe C5-dependent thrombotic microangiopathy upon kidney-specific complement activation, mimicking aHUS.

Conclusions:

• Subtotal FH deficiency can cause spontaneous C3G.
• Complement factor H deficiency in hepatocytes contributes to C3G and aHUS pathogenesis.
• The development of aHUS in this model is dependent on complement component C5 activation within the kidney following a trigger.