C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis

Area of Science:

• Immunology
• Nephrology
• Pathology

Background:

• Inflammatory glomerulonephritis (GN) involves glomerular endothelial injury.
• The complement system, particularly the C5b-9 membrane attack complex, plays a role in inflammatory diseases.
• Glomerular endothelial cell (GEN) apoptosis is a key feature of GN.

Purpose of the Study:

• To investigate the specific role of the C5b-9 membrane attack complex in experimental inflammatory GN.
• To determine the impact of C5b-9 on glomerular endothelial cell apoptosis and kidney function.

Main Methods:

• Two models of GN were induced in complement-sufficient (C+), C6-deficient (C6-), and complement-depleted (CVF) rats.
• Glomerular endothelial cell (GEN) apoptosis was assessed in response to concanavalin A (Con A) or anti-GEN antibody.
• The effect of inhibiting the complement regulatory protein CD59 was examined.

Main Results:

• C5b-9 mediated GEN apoptosis in both Con A GN and immune-mediated thrombotic microangiopathy (ITM) models.
• Complement depletion (CVF) significantly reduced GEN apoptosis.
• C6-deficient rats were protected from GEN loss, confirming C5b-9 dependence.
• Inhibition of CD59 increased GEN apoptosis.
• Preventing GEN apoptosis preserved endothelial integrity and renal function in Con A GN.

Conclusions:

• The C5b-9 membrane attack complex is a critical mediator of glomerular endothelial cell apoptosis in inflammatory GN.
• Targeting C5b-9 or enhancing complement regulation may offer therapeutic strategies for GN.
• These findings have implications for diseases involving antiendothelial cell antibodies.