Galactose-Deficient IgA<sub>1</sub>-Containing Immune Complexes Deposit with Complementary Activity in Mesangium Through Endothelial Cell Injuries
October 22, 2020 | 10:00 AM - 12:00 PM
Click an icon below to load this item into your calendar. Please note that times are exported as Coordinated Universal Time (UTC). Time zone help.
Galactose-Deficient IgA1-Containing Immune Complexes Deposit with Complementary Activity in Mesangium Through Endothelial Cell Injuries
- Glomerular Diseases: IgA, C3G, and FSGS
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
- Makita, Yuko, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Suzuki, Hitoshi, Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan
- Nakano, Daisuke, Department of Pharmacology, Kagawa University, Kagawa, Japan
- Kano, Toshiki, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Nishiyama, Akira, Department of Pharmacology, Kagawa University, Kagawa, Japan
- Suzuki, Yusuke, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
IgAN is defined by the presence of dominant mesangial IgA1 immune deposits, accompanied by C3 deposits, and deposition of IgA1 includes galactose-deficient IgA1 (Gd-IgA1). However, the pathogenic role of Gd-IgA1-containing IC with regard to mesangial immune deposits are still unclear. The endothelial surface glycocalyx modulates microvascular function. Loss of the glomerular endothelial glycocalyx is involved in albuminuria. In present study, we hypothesized that Gd-IgA1-containing IC deposit in mesangium through glomerular endothelial cell injuries.
Gd-IgA1 and recombinant anti-glycan IgG were used to form IC (Gd-IgA1-IgG IC) to inject i.v into nude mice. After various time intervals, mice were sacrificed and kidney was harvested to determine mesangial deposition and kidney injuries. To investigate that Gd-IgA1-IgG IC stimulation increases permeability of glomerular microvascular resulted in renal injuries, the renal microvascular endothelial glycocalyx removal was estimated by real-time glycocalyx imaging. Furthermore, human renal glomerular endothelial cells (HRGEC) were co-cultured with Gd-IgA1 alone or Gd-IgA1-IgG IC for 72 h to assess the potential capacity of these IC to activate endothelial cells.
After injection of Gd-IgA1-IgG IC, but not Gd-IgA1 only induced proteinuria and hematuria in nude mice. Gd-IgA1-IgG IC deposited with murine C3 in the mesangium as well as subendothelial area of the glomerular capillaries. Furthermore, electron microscopic examination showed that injection of Gd-IgA1-IgG IC induced endothelial injuries. In fact, real-time glycocalyx imaging showed that renal microvascular glycocalyx were reduced after injection of Gd-IgA1-IgG IC in nude mice.
After co-culture of Gd-IgA1-IgG IC with HRGEC, transcript levels of endothelial adhesion factors such as ICAM-1, VCAM-1 and E-selectin were significantly upregulated (P<0.01). Transcript levels of TNFα and IL-6, proinflammatory mediators which are able to induce the expression of adhesion factors on endothelial cells, were also increased (P<0.01).
Present data suggested that Gd-IgA1-containg IC deposition and subsequent complement activation may induce endothelial damage and overexpression of pathogenic cytokines and adhesion molecules resulting in glomerular injuries in IgAN.