Complement regulation in renal disease models

Area of Science:

• Immunology and Nephrology
• Complement system biology
• Molecular and cellular mechanisms of kidney disease

Background:

• The complement system is crucial for innate and adaptive immunity.
• Complement regulatory proteins (CRPs) like factor H (fH), decay-accelerating factor, and membrane cofactor protein tightly control complement activation.
• Dysregulation of CRPs is implicated in various kidney diseases.

Purpose of the Study:

• To elucidate the roles of complement regulatory proteins (CRPs) in kidney pathophysiology.
• To understand how CRP deficiencies contribute to distinct kidney pathologies.
• To explore the interplay between CRPs and different complement pathways in glomerular diseases.

Main Methods:

• Analysis of animal models with genetic deficiencies or alterations in specific CRPs (e.g., fH, Crry).
• Investigation of complement activation patterns (fluid phase vs. local) in response to CRP defects.
• Correlation of complement dysregulation with specific kidney pathologies such as dense deposit disease, thrombotic microangiopathy, and tubulointerstitial nephritis.

Main Results:

• Mice lacking fH exhibit excessive C3 activation and deposition in glomerular capillary walls (GCW), mimicking dense deposit disease.
• Altered fH targeting leads to local GCW activation and thrombotic microangiopathy.
• Defective Crry causes alternative pathway dysregulation in the tubulointerstitium, resulting in TMA, acute kidney injury, and nephritis.

Conclusions:

• CRPs are critical for preventing excessive complement activation in the kidney.
• Defective CRPs, particularly fH in the GCW and Crry in the tubulointerstitium, precipitate distinct kidney pathologies.
• Acquired alterations in CRPs, potentially due to cellular injury or autoantibodies, are common and influence disease development.