Glomerular mesangial cells derived complement factor H regulates complement activation, influences cell...

Area of Science:

• Nephrology
• Immunology
• Cell Biology

Background:

• Complement factor H (CFH) is a key regulator of the alternative complement pathway, primarily produced by the liver.
• Recent research suggests CFH has functions beyond complement activation, particularly in organs susceptible to complement-mediated damage like the kidney.
• Glomerular mesangial cells (GMCs) are intrinsic kidney cells and potential sources of complement proteins.

Purpose of the Study:

• To investigate the role and functions of CFH specifically within glomerular mesangial cells.
• To determine if GMC-derived CFH has unique properties compared to exogenous CFH.
• To explore both the canonical and non-canonical functions of CFH in GMCs.

Main Methods:

• Analysis of single-cell sequencing data to identify kidney cells with high CFH expression.
• Confirmation of CFH expression in primary human glomerular mesangial cells (pHGMCs).
• Experimental manipulation of CFH levels (silencing and overexpression) in pHGMCs, followed by exposure to IgA nephropathy (IgAN) immune complexes and assessment of complement deposition, cell proliferation markers, and cytoskeleton dynamics.

Main Results:

• Glomerular mesangial cells were identified as the primary kidney cells expressing CFH.
• Exposure to IgAN immune complexes reduced CFH mRNA expression in pHGMCs.
• Silencing CFH increased complement deposition (C3c, C5b-9), while CFH overexpression reduced it.
• pHGMC-derived CFH was more effective in regulating complement activation than exogenous CFH.
• GMC-derived CFH promoted cell proliferation by modulating cell cycle regulators (KLF4, p21, CDK, cyclins) and influenced cell motility via Cdc42 and actin cytoskeleton.
• Exogenous CFH did not affect pHGMC proliferation or cytoskeleton.

Conclusions:

• Glomerular mesangial cells intrinsically produce CFH, which plays a vital role in regulating complement activation within the kidney.
• Locally produced CFH by GMCs exhibits non-canonical functions, including promoting cell proliferation and maintaining cytoskeletal integrity.
• These findings highlight a specialized, intrinsic role for CFH in glomerular mesangial cells beyond its systemic complement regulatory function.