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Macrophage Fc receptor activity modulates mesangial cell proliferation and matrix synthesis
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park 11042.
Abstract:
Substantial in vivo evidence exists to implicate the macrophage (M phi) in modulating mesangial expansion and glomerulosclerosis (GS) following renal injury. We studied in an in vitro system how M phi activation via Fc-receptor-mediated endocytosis, such as occurs in immune complex-mediated disease states, may influence the effect of M phi secretory products (MSP) on mesangial cell (MC) proliferation and matrix synthesis. MSP from M phi incubated with immunoglobulin G (IgG) complexes caused significantly greater (P < 0.001) enhancement of MC [3H]thymidine incorporation compared with MSP from unstimulated M phi or from M phi activated via nonspecific endocytosis (P < 0.001). MSP from M phi incubated with IgG complexes plus the inhibitor of endocytosis cytochalasin B showed an attenuated effect on MC proliferation (P < 0.02). MSP were also found to enhance MC matrix synthesis (P < 0.001). These data demonstrate that MSP can play a direct role in mesangial expansion by increasing both MC proliferation and matrix synthesis. Surface binding alone of IgG complexes may not be sufficient to activate M phi and enhance their mitogenic effect on MC as endocytosis appears to be required. These findings lend in vitro support to a potential role for the M phi in the process of mesangial expansion and GS following renal injury.
Insights
Activated macrophages significantly increase mesangial cell proliferation and matrix synthesis, driving kidney disease progression. Endocytosis of immune complexes by macrophages is crucial for this effect, highlighting a key mechanism in glomerulosclerosis.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Macrophages (M phi) are implicated in mesangial expansion and glomerulosclerosis (GS) after kidney injury.
- Immune complex-mediated diseases involve M phi activation via Fc-receptor-mediated endocytosis.
Purpose of the Study:
- To investigate how M phi activation influences their secretory products' effects on mesangial cell (MC) proliferation and matrix synthesis in vitro.
- To determine the role of endocytosis in M phi-mediated MC responses.
Main Methods:
- Cultured M phi were activated with immunoglobulin G (IgG) complexes.
- Macrophage secretory products (MSP) were applied to MC cultures.
- MC proliferation was assessed via [3H]thymidine incorporation.
- Effects were compared between M phi activated via Fc-receptor-mediated endocytosis and nonspecific endocytosis, with and without endocytosis inhibitors.
Main Results:
- MSP from M phi incubated with IgG complexes significantly enhanced MC proliferation compared to unstimulated M phi (P < 0.001).
- Endocytosis inhibition (cytochalasin B) attenuated the proliferative effect of MSP (P < 0.02).
- MSP also significantly enhanced MC matrix synthesis (P < 0.001).
Conclusions:
- Macrophage secretory products directly contribute to mesangial expansion by increasing MC proliferation and matrix synthesis.
- Fc-receptor-mediated endocytosis of immune complexes by M phi is required for maximal mitogenic effects on MC.
- These findings support a role for M phi in glomerulosclerosis pathogenesis.