Gain-of-function factor H-related 5 protein impairs glomerular complement regulation resulting in kidney damage

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Genetic variations in factor H-related (FHR) genes are linked to C3 glomerulopathy (C3G), a complement-mediated kidney disease.
• Currently, no definitive treatments exist for C3G, leading to end-stage renal disease in many patients.
• CFHR5 nephropathy, characterized by mutant FHR5 protein accumulation and glomerular C3 deposition, exemplifies C3G pathogenesis.

Purpose of the Study:

• To model CFHR5 nephropathy in mice to understand how abnormal FHR proteins cause C3G.
• To investigate the pathogenic mechanism of mutant FHR5 protein in C3G.
• To evaluate the therapeutic potential of FH-derived molecules in a mouse model of C3G.

Main Methods:

• Developed a mouse model of CFHR5 nephropathy by coexpressing human factor H (FH) and a mutant FHR5 protein (FHR5mut).
• Assessed glomerular C3 deposition in mice expressing human FH with FHR5mut versus normal FHR5.
• Administered adeno-associated virus vector-delivered homodimeric mini-FH to mice with FHR5mut-induced C3 deposition.

Main Results:

• Mice coexpressing human FH and FHR5mut developed glomerular C3 deposition, unlike those with normal FHR5.
• The FHR5mut exhibited a dominant gain-of-function effect, triggering C3 deposition when administered.
• Homodimeric mini-FH reduced glomerular C3 deposition in the presence of FHR5mut, demonstrating therapeutic efficacy.

Conclusions:

• Mutant FHR5 protein directly causes C3G by disrupting kidney complement homeostasis.
• FH-derived molecules with enhanced C3 binding are promising therapeutic agents for C3G associated with abnormal FHR proteins.
• Targeting FHR5 offers a potential strategy for treating complement-mediated kidney injury.